Journal of Blood Research & Hematologic Diseases.

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Research Article, J Blood Res Hematol Dis Vol: 2 Issue: 1

Haemophilia B PMS1 Gene SNPs Predictions through Insilico Approach at Proteomics Levels

Hiba Siddig Ibrahim*

The National Ribat University, Department of Microbiology, Faculty of Medical Laboratory Science, The National Ribat University, Sudan

*Corresponding Author : Hiba Siddig Ibrahim Mustafa
Department of Microbiology, Faculty of Medical Laboratory Science, The National Ribat University, Sudan
Tel: 249155772782
E-mail: [email protected]

Received: December 22, 2016 Accepted: January 05, 2017 Published: January 11, 2017

Citation: Ibrahim HS (2017) Haemophilia B PMS1 Gene SNPs Predictions through In-silico Approach at Proteomics Levels. J Blood Res Hematol Dis 2:1.

Abstract

Hemophilia is one of the important hereditary disease that leading to deficiency in some clotting factors due to gene mutations beside this it related most important hematologic parts; anemia, the aim of this study is to identify the PMS1 (hemophilia B) gene SNPs and to predict mutation effects of this gene at the proteomic level, through in silico tools such as proven, sift, polyphen-2, I mutant suite-3, SNPs & GO, finally Meta-snp prediction. A according to these predictions tools & their confirmations I found that PMS1 gene SNPs showed damaging prediction which was considered as clinical manifestation in this study beside these a lots of SNPs illustrate decreasing in protein functionality; unfortunately 26 SNPs showed prediction results just with sift & proven predictions software and these explain why they were excluded from this study with those showed benign predictions by polyphen-2, in addition to confirmation of ORMDL1 gene SNPs that located at the same PMS1 gene chromosome had the same clinical effect such as PMS1 gene SNPs.

Keywords: Haemophilia B; Clotting factors; Meta-snp prediction

Introduction

Hemophilia B is characterized by deficiency in factor IX clotting activity due to mutation in factor IX gene, that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. Hemophilia B is phenotypically indistinguishable from hemophilia A, it was first recognized as a different kind of hemophilia in 1952 with additional name Christmas disease; named after Stephen Christmas, the first patient who described with this disease. According to the level of factor IX clotting activity beside age of patients and frequency of bleeding episodes hemophilia are divided to 3 levels; mild, moderate and severe [1,2].

Individuals with mild hemophilia B do not have spontaneous bleeding and they often diagnosed later in their life with bleeding tendency once a year or once every ten years; however, without pre- and post-operative treatment, abnormal bleeding can happens with surgery or tooth extractions, while in moderate hemophilia B they have spontaneous bleeding with prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies from once a month to once a year, but in severe hemophilia B, spontaneous joint or deep-muscle bleeding is the most frequent symptom, those individuals are usually diagnosed during the first two years of life; without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month [1].

Genetically; factor IX gene is located on the X chromosome (Xq27.1-q27.2), it’s an X-linked recessive trait, which explain why only males usually affected. In addition in 1990, George Brownlee and Merlin Crossley showed that two sets of genetic mutations were preventing two key proteins from attaching to the DNA of people with a rare and unusual form of haemophilia B and haemophilia B Leyden, those people are suffering from excessive bleeding in childhood but it became rare after puberty, This deficiency lead to turning off the gene that produces clotting factor IX, which prevents excessive bleeding [2,3].

In this study I used different computational methods to identify the PMS1 (hemophilia B) gene SNPs and to predict mutation effects at the proteomic level.

Materials and Methods

Hemophilia B retrieved sequence

Hemophilia B sequence was retrieved from NCBI through SNP search (https://www.ncbi.nlm.nih.gov/snp/?term=haemeophilia%20B); rs1145234 [Homo sapiens] in chromosome two (Chromosome: 2:189867833) for PMS1 gene, it is intr on variant, missense, NC transcript variant Allele Origin: G (germline)/T (germline)/C (germline), this was selected from total SNPs 2347417 results.

Proven

Proven protein batch for human (PROVEAN v1.1.3.) (http://provean.jcvi.org/index.php) was selected in this study; PROVEAN is abbreviation for Protein Variation Effect Analyzer, its useful software for filtering sequence variants to identify nonsynonymous or indel variants that are predicted to be functionally important [4-6].

Sift Prediction (SIFT - Predict effects of nonsynonmous / missense variants)

(http://sift.bii.a-star.edu.sg/) SIFT dbSNP 138 was selected from batch tools from SIFT Sorting Intolerant From Tolerant software to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids.

PolyPhen-2 (Polymorphism phenotyping v2)

PolyPhen-2 prediction of functional effects of human nsSNPs (http://genetics.bwh.harvard.edu/pph2/index.shtml) was used to predict the impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations [7-10].

I-Mutant suite

I mutant.3 (http://gpcr2.biocomp.unibo.it/cgi/predictors/IMutant3.0/I-Mutant3.0.cgi) was used to predict protein stability changes upon single point mutation from: Protein Structure / Protein Sequence and also prediction of disease associated with single point mutation from Protein Sequence [11-13].

SNPs and GO

SNPs & GO (http://snps.biofold.org/snps-and-go/snps-and-go.html) was used to predicting a disease associated variations by GO terms through SVM-based classifier, which takes in input protein sequence, profile and functional information to give output as disease-related or neutral with RI & scores [14-19].

Meta-SNPMeta-SNP (Meta-predictor of disease causing variants) (http://snps.biofold.org/meta-snp/#) was used to confirm the results of previous methods; PANTHER, PhD-SNP, SIFT and SNAP, through the non-synonymous SNVs (nsSNVs), that’s results in a single amino acid substitutions and may affect protein functions that lead to causing a disease [20-22].

Results

Proven

The total of 143 nsSNPs which was predicted by Proven prediction tools showed 83 snSNPs which are deleterious with in these 81 nsSNPs were damaging and 3 nsSNPs were tolerated according to sift prediction while 45 nsNSPs showed neutral prediction by proven with 33nsSNPs were damaging and 12 were tolerated according to Sift prediction but 15 snSNPs they were considered benign by polyphen-2 which were excluded from this study, please see details below with Table 1.

In rs1145232; proven prediction showed 5 nsSNPs were deleterious with sift prediction damaging for all.

In rs5742973, according to proven prediction, 1 nsSNPs showed deleterious with sift prediction damaging.

In rs56309301; 1 nsSNPs showed neutral prediction by proven while sift prediction showed tolerated.

In rs61756360; according to proven prediction, 1 nsSNPs showed deleterious with sift prediction showed damaging, in rs111254723; 4 nsSNPs showed deleterious according to proven with sift prediction tolerated for all of them, in rs142159998; 3 nsSNPs showed deleterious by proven while sift prediction showed damaging for all, in rs143010673; according to proven prediction, 3 nsSNPs showed deleterious with sift prediction damaging for all, in rs143554211; 6 nsSNPs showed neutrals according to proven prediction with sift prediction showed damaging for all, in rs143686298; proven prediction showed 2 nsSNPs with neutrals prediction and damaging prediction by sift for all, in rs145103030; 5 nsSNPs showed deleterious according to proven prediction and damaging by sift prediction, in rs145521752; 6 nsSNPs where deleterious by proven prediction while sift prediction showed damaging for all, in rs147901996; 3 nsSNPs they were deleterious by proven with damaging sift prediction.

In rs148745528; 5 nsSNPs showed deleterious prediction by proven with damaging sift prediction predicts, in rs185306467; 3 nsSNPs showed deleterious prediction by proven with sift prediction damaging for the three, in rs188947672; 4 nsSNPs showed neutrals proven prediction and sift prediction damaging for all, in rs189785572; proven prediction showed 2 nsSNPs with neutral prediction and damaging sift prediction for both, in rs193252599; proven predictions showed 2 nsSNPs predict neutral with sift prediction tolerated and damaging for each one of them, in rs199892342; proven prediction showed 1 nsSNPs with neutral prediction while sift prediction showed damaging predict, in rs200172149; according to proven prediction 1 nsSNPs showed neutral predict with tolerated sift prediction.

In rs200244068; proven prediction showed 2 nsSNPs deleterious in addition to damaging sift prediction for both, in rs200395679; proven prediction showed 1 nsSNPs showed neutral with damaging sift prediction, in rs200919195; according to proven prediction 1 nsSNPs showed neutral prediction with tolerated sift prediction, in rs201944922; 1 nsSNPs showed deleterious according to proven prediction while sift prediction showed damaging effect, in rs368282144; 5 nsSNPs showed deleterious proven prediction while sift prediction showed 3 nsSNPs with damaging and 2 nsSNPs they were tolerated.

rs369226504; according to proven prediction, 3 nsSNPs showed deleterious with 3 nsSNPs neutral while for sift prediction all of them showed damaging, in rs369814333; in proven prediction, 1 nsSNPs showed deleterious and the second one showed neutral with tolerated sift prediction for both, rs369909997; by proven prediction showed 1 nsSNPs neutral and tolerated sift prediction, rs370084230; 1 nsSNPs showed deleterious by proven prediction and damaging sift prediction, in rs370300640; According to proven prediction, 1 nsSNPs showed deleterious with sift prediction damaging, in rs370578519; 4 nsSNPs showed deleterious by proven prediction with damaging sift prediction for all, in rs370668897; 1 nsSNPs showed deleterious according to proven prediction and damaging sift prediction, in rs371745827; 6 nsSNPs showed deleterious by proven prediction and all of them were damaging by sift prediction, in rs371999153; 1nsSNPs showed deleterious by proven prediction and damaging by sift prediction, in rs372752293; 2 nsSNPs showed deleterious according to proven and damaging by sift prediction, in rs374222815; 1 nsSNPs showed neutral by proven prediction and damaging according to sift prediction, in rs374879205; 5 nsSNPs showed deleterious according to proven prediction, with damaging sift prediction for all five, in rs375020232, proven prediction showed 6 nsSNPs with deleterious predict and damaging predicts by sift prediction, in rs375164425; 2 nsSNPs showed neutral predict by proven and tolerated predicts by sift prediction.

In rs375553851; 4 nsSNPs showed neutral predicts by proven prediction but 1 nsSNPs deleterious predict while the forth were had damaging predicts by sift prediction, another rs375640863; showed 4 nsSNPs with deleterious predicts by proven predict and damaging by sift prediction, in rs377024581; according to proven prediction 1nsSNPs showed deleterious predict with damaging sift prediction, rs377266054; proven prediction showed 2 nsSNPs with neutral predicts in addition to damaging sift prediction and the last one rs377603311; showed 4 nsSNPs with deleterious predicts by proven prediction and 1 nsSNPS with neutral predict while sift prediction showed damaging for all (Table 1).

SNP Organism Amino Acid Change Proven Prediction Score Proven Prediction (Cutoff=-2.5) Proven #SEQ Sift Score Sift Prediction (Cutoff=0.05)
rs1145232 Homo_sapiens /GRCh37.74 G286R -3.96 Deleterious 125 0 Damaging
rs1145232 Homo_sapiens /GRCh37.74 G325R -5.21 Deleterious 95 0 Damaging
rs1145232 Homo_sapiens /GRCh37.74 G440R -5.62 Deleterious 94 0 Damaging
rs1145232 Homo_sapiens /GRCh37.74 G501R -5.49 Deleterious 94 0 Damaging
rs1145232 Homo_sapiens /GRCh37.74 G462R -5.5 Deleterious 93 0 Damaging
rs5742973 Homo_sapiens /GRCh37.74 E27Q -2.83 Deleterious 93 0 Damaging
rs56309301 Homo_sapiens /GRCh37.74 N243T -1.88 Neutral 84 0.259 Tolerated
rs61756360 Homo_sapiens /GRCh37.74 T75I -5.9 Deleterious 93 0 Damaging
rs111254723 Homo_sapiens /GRCh37.74 Y550C -0.73 Neutral 125 0.08 Tolerated
rs111254723 Homo_sapiens /GRCh37.74 Y751C -0.59 Neutral 95 0.061 Tolerated
rs111254723 Homo_sapiens /GRCh37.74 Y888C -0.57 Neutral 93 0.065 Tolerated
rs111254723 Homo_sapiens /GRCh37.74 Y927C -0.57 Neutral 92 0.064 Tolerated
rs142159998 Homo_sapiens /GRCh37.74 R721C -4.46 Deleterious 94 0 Damaging
rs142159998 Homo_sapiens /GRCh37.74 R844C -4.91 Deleterious 93 0.039 Damaging
rs142159998 Homo_sapiens /GRCh37.74 R883C -4.87 Deleterious 92 0.039 Damaging
rs143010673 Homo_sapiens /GRCh37.74 W22C -10.28 Deleterious 95 0.001 Damaging
rs143010673 Homo_sapiens /GRCh37.74 W137C -10.66 Deleterious 94 0.001 Damaging
rs143010673 Homo_sapiens /GRCh37.74 W198C -10.93 Deleterious 92 0.001 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R695C -1.23 Neutral 95 0.03 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R494C -1.35 Neutral 125 0.028 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R259C -1.8 Neutral 84 0.018 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R832C -1.38 Neutral 93 0.02 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R871C -1.34 Neutral 92 0.019 Damaging
rs143554211 Homo_sapiens /GRCh37.74 R709C -1.24 Neutral 94 0.028 Damaging
rs143686298 Homo_sapiens /GRCh37.74 P732T -1.75 Neutral 93 0.044 Damaging
rs143686298 Homo_sapiens /GRCh37.74 P771T -1.75 Neutral 92 0.036 Damaging
rs145103030 Homo_sapiens /GRCh37.74 R542C -5.3 Deleterious 125 0.007 Damaging
rs145103030 Homo_sapiens /GRCh37.74 R880C -4.11 Deleterious 93 0.001 Damaging
rs145103030 Homo_sapiens /GRCh37.74 R743C -4.82 Deleterious 95 0.001 Damaging
rs145103030 Homo_sapiens /GRCh37.74 R919C -4.15 Deleterious 92 0.001 Damaging
rs145103030 Homo_sapiens /GRCh37.74 R757C -3.4 Deleterious 94 0.004 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E813A -3.73 Deleterious 93 0.007 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E852A -3.73 Deleterious 92 0.007 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E690A -3.51 Deleterious 94 0 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E676A -4.02 Deleterious 95 0 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E475A -4.84 Deleterious 125 0 Damaging
rs145521752 Homo_sapiens /GRCh37.74 E240A -4.7 Deleterious 84 0.006 Damaging
rs147901996 Homo_sapiens /GRCh37.74 N145S -3.55 Deleterious 95 0.02 Damaging
rs147901996 Homo_sapiens /GRCh37.74 N106S -3.38 Deleterious 125 0.02 Damaging
rs147901996 Homo_sapiens /GRCh37.74 N260S -2.98 Deleterious 94 0.017 Damaging
rs148745528 Homo_sapiens /GRCh37.74 K99E -3.77 Deleterious 125 0 Damaging
rs148745528 Homo_sapiens /GRCh37.74 K138E -3.61 Deleterious 95 0 Damaging
rs148745528 Homo_sapiens /GRCh37.74 K253E -3.38 Deleterious 94 0 Damaging
rs148745528 Homo_sapiens /GRCh37.74 K275E -3.7 Deleterious 93 0 Damaging
rs148745528 Homo_sapiens /GRCh37.74 K314E -3.47 Deleterious 92 0 Damaging
rs185306467 Homo_sapiens /GRCh37.74 I21N -4.98 Deleterious 95 0.001 Damaging
rs185306467 Homo_sapiens /GRCh37.74 I136N -5.74 Deleterious 94 0.001 Damaging
rs185306467 Homo_sapiens /GRCh37.74 I197N -6.01 Deleterious 92 0.001 Damaging
rs188947672 Homo_sapiens /GRCh37.74 L706V -0.9 Neutral 94 0.009 Damaging
rs188947672 Homo_sapiens /GRCh37.74 L728V -1.1 Neutral 93 0.045 Damaging
rs188947672 Homo_sapiens /GRCh37.74 L591V -1.25 Neutral 95 0.036 Damaging
rs188947672 Homo_sapiens /GRCh37.74 L155V -1.35 Neutral 84 0.027 Damaging
rs189785572 Homo_sapiens /GRCh37.74 A501S -0.81 Neutral 94 0.028 Damaging
rs189785572 Homo_sapiens /GRCh37.74 A386S -0.89 Neutral 95 0.023 Damaging
rs193252599 Homo_sapiens /GRCh37.74 E168K -1.7 Neutral 84 0.251 Tolerated
rs193252599 Homo_sapiens /GRCh37.74 E604K -0.95 Neutral 95 0.014 Damaging
rs199892342 Homo_sapiens /GRCh37.74 V671A -2.18 Neutral 95 0.002 Damaging
rs200172149 Homo_sapiens /GRCh37.74 T202A -1.3 Neutral 84 0.06 Tolerated
rs200244068 Homo_sapiens /GRCh37.74 D106G -4.65 Deleterious 94 0.004 Damaging
rs200244068 Homo_sapiens /GRCh37.74 D167G -4.82 Deleterious 92 0.003 Damaging
rs200395679 Homo_sapiens /GRCh37.74 A104T -2.37 Neutral 92 0.004 Damaging
rs200919195 Homo_sapiens /GRCh37.74 Y195F -1.26 Neutral 84 0.204 Tolerated
rs201944922 Homo_sapiens /GRCh37.74 L4S -5.37 Deleterious 93 0.001 Damaging
rs368282144 Homo_sapiens /GRCh37.74 P299A -4.51 Deleterious 125 0 Damaging
rs368282144 Homo_sapiens /GRCh37.74 P338A -3.74 Deleterious 95 0 Damaging
rs368282144 Homo_sapiens /GRCh37.74 P453A -3.66 Deleterious 94 0 Damaging
rs368282144 Homo_sapiens /GRCh37.74 P514A -4.22 Deleterious 94 0.094 Tolerated
rs368282144 Homo_sapiens /GRCh37.74 P475A -4.1 Deleterious 93 0.144 Tolerated
rs369226504 Homo_sapiens /GRCh37.74 T202R -3.15 Deleterious 84 0.006 Damaging
rs369226504 Homo_sapiens /GRCh37.74 T437R -2.26 Neutral 125 0.013 Damaging
rs369226504 Homo_sapiens /GRCh37.74 T775R -2.59 Deleterious 93 0.008 Damaging
rs369226504 Homo_sapiens /GRCh37.74 T638R -2.37 Neutral 95 0.007 Damaging
rs369226504 Homo_sapiens /GRCh37.74 T814R -2.79 Deleterious 92 0.008 Damaging
rs369226504 Homo_sapiens /GRCh37.74 T652R -2.17 Neutral 94 0.011 Damaging
rs369814333 Homo_sapiens /GRCh37.74 N81I -2.68 Deleterious 84 0.07 Tolerated
rs369814333 Homo_sapiens /GRCh37.74 N517I -1.9 Neutral 95 0.071 Tolerated
rs369909997 Homo_sapiens /GRCh37.74 N228D -1.16 Neutral 84 0.418 Tolerated
rs370084230 Homo_sapiens /GRCh37.74 R10Q -2.57 Deleterious 94 0 Damaging
rs370300640 Homo_sapiens /GRCh37.74 G91S -6 Deleterious 93 0 Damaging
rs370578519 Homo_sapiens /GRCh37.74 P661L -4.41 Deleterious 93 0.003 Damaging
rs370578519 Homo_sapiens /GRCh37.74 P524L -3.78 Deleterious 95 0.003 Damaging
rs370578519 Homo_sapiens /GRCh37.74 P700L -4.38 Deleterious 92 0.003 Damaging
rs370578519 Homo_sapiens /GRCh37.74 P639L -4.03 Deleterious 94 0.003 Damaging
rs370668897 Homo_sapiens /GRCh37.74 K51T -4.09 Deleterious 94 0.003 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R435C -5.23 Deleterious 125 0 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R773C -4.84 Deleterious 93 0 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R636C -4.44 Deleterious 95 0 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R812C -5.11 Deleterious 92 0 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R650C -4.88 Deleterious 94 0 Damaging
rs371745827 Homo_sapiens /GRCh37.74 R200C -6.48 Deleterious 84 0 Damaging
rs371999153 Homo_sapiens /GRCh37.74 W49C -11.6 Deleterious 164 0 Damaging
rs372752293 Homo_sapiens /GRCh37.74 T110R -5.74 Deleterious 93 0 Damaging
rs372752293 Homo_sapiens /GRCh37.74 T49R -5.48 Deleterious 94 0 Damaging
rs374222815 Homo_sapiens /GRCh37.74 V505M -1.48 Neutral 125 0 Damaging
rs374222815 Homo_sapiens /GRCh37.74 V706M -1.81 Neutral 95 0 Damaging
rs374222815 Homo_sapiens /GRCh37.74 V843M -1.88 Neutral 93 0.003 Damaging
rs374222815 Homo_sapiens /GRCh37.74 V882M -1.81 Neutral 92 0.002 Damaging
rs374222815 Homo_sapiens /GRCh37.74 V720M -1.52 Neutral 94 0 Damaging
rs374879205 Homo_sapiens /GRCh37.74 P512A -3.12 Deleterious 125 0 Damaging
rs374879205 Homo_sapiens /GRCh37.74 P713A -3.57 Deleterious 95 0.013 Damaging
rs374879205 Homo_sapiens /GRCh37.74 P850A -3.79 Deleterious 93 0 Damaging
rs374879205 Homo_sapiens /GRCh37.74 P889A -3.75 Deleterious 92 0.014 Damaging
rs374879205 Homo_sapiens /GRCh37.74 P727A -3.24 Deleterious 94 0.025 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R435L -3.67 Deleterious 125 0 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R773L -4.39 Deleterious 93 0 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R636L -4.12 Deleterious 95 0 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R812L -4.56 Deleterious 92 0 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R650L -4.15 Deleterious 94 0 Damaging
rs375020232 Homo_sapiens /GRCh37.74 R200L -5.43 Deleterious 84 0 Damaging
rs375164425 Homo_sapiens /GRCh37.74 I57V -0.48 Neutral 125 0.127 Tolerated
rs375164425 Homo_sapiens /GRCh37.74 I96V -0.65 Neutral 95 0.137 Tolerated
rs375553851 Homo_sapiens /GRCh37.74 N703H -1.98 Neutral 94 0.005 Damaging
rs375553851 Homo_sapiens /GRCh37.74 N152H -2.93 Deleterious 84 0.01 Damaging
rs375553851 Homo_sapiens /GRCh37.74 N588H -2.17 Neutral 95 0.005 Damaging
rs375553851 Homo_sapiens /GRCh37.74 N725H -2.16 Neutral 93 0.012 Damaging
rs375553851 Homo_sapiens /GRCh37.74 N764H -2.23 Neutral 92 0.012 Damaging
rs375640863 Homo_sapiens /GRCh37.74 D435G -3.14 Deleterious 94 0.004 Damaging
rs375640863 Homo_sapiens /GRCh37.74 D281G -2.9 Deleterious 125 0.004 Damaging
rs375640863 Homo_sapiens /GRCh37.74 D320G -3.01 Deleterious 95 0.004 Damaging
rs375640863 Homo_sapiens /GRCh37.74 D457G -3.22 Deleterious 93 0.003 Damaging
rs377024581 Homo_sapiens /GRCh37.74 D56G -6.83 Deleterious 93 0 Damaging
rs377266054 Homo_sapiens /GRCh37.74 E511V -2.42 Neutral 95 0.01 Damaging
rs377266054 Homo_sapiens /GRCh37.74 E626V -2.11 Neutral 94 0.008 Damaging
rs377603311 Homo_sapiens /GRCh37.74 R844H -2.92 Deleterious 93 0.003 Damaging
rs377603311 Homo_sapiens /GRCh37.74 R883H -2.96 Deleterious 92 0.003 Damaging
rs377603311 Homo_sapiens /GRCh37.74 R721H -2.11 Neutral 94 0 Damaging
rs377603311 Homo_sapiens /GRCh37.74 R707H -3.3 Deleterious 95 0.003 Damaging
rs377603311 Homo_sapiens /GRCh37.74 R506H -3.59 Deleterious 125 0 Damaging

Table 1: Illustrate proven prediction with sift results for SNPs.

Sift prediction

A total numbers of 127 out of 143 nsSNPs were considered deleterious by sift prediction in addition to 15 other snSNPs that was also deleterious too but they excluded from this study due to they considered benign according to polyphen-2 software with 1 snSNPs in rs188947672 at position L155V which represented the only SNPs that showed tolerated prediction by sift (Table 2).

SNP Organism Amino Acid Change Sift Score Sift Prediction Polyphen Resuit Polyphen Score
rs1145232 Homo_sapiens /GRCh37.74 G286R 0 DELETERIOUS PROBABLY DAMAGING 1
rs1145232 Homo_sapiens /GRCh37.74 G325R 0 DELETERIOUS - -
rs1145232 Homo_sapiens /GRCh37.74 G440R 0 DELETERIOUS PROBABLY DAMAGING 1
rs1145232 Homo_sapiens /GRCh37.74 G501R 0 DELETERIOUS PROBABLY DAMAGING 1
rs1145232 Homo_sapiens /GRCh37.74 G462R 0.002 DELETERIOUS PROBABLY DAMAGING 1
rs5742973 Homo_sapiens /GRCh37.74 E27Q 0 DELETERIOUS PROBABLY DAMAGING 1
rs56309301 Homo_sapiens /GRCh37.74 N243T 0.011 DELETERIOUS POSSIBLY DAMAGING 0.873
rs61756360 Homo_sapiens /GRCh37.74 T75I 0 DELETERIOUS PROBABLY DAMAGING 1
rs111254723 Homo_sapiens /GRCh37.74 Y550C 0.037 DELETERIOUS POSSIBLY DAMAGING 0.899
rs111254723 Homo_sapiens /GRCh37.74 Y751C 0.041 DELETERIOUS - -
rs111254723 Homo_sapiens /GRCh37.74 Y888C 0.046 DELETERIOUS POSSIBLY DAMAGING 0.898
rs111254723 Homo_sapiens /GRCh37.74 Y927C 0.048 DELETERIOUS POSSIBLY DAMAGING 0.833
rs142159998 Homo_sapiens /GRCh37.74 R721C 0.038 DELETERIOUS POSSIBLY DAMAGING 0.655
rs142159998 Homo_sapiens /GRCh37.74 R844C 0.04 DELETERIOUS PROBABLY DAMAGING 0.997
rs142159998 Homo_sapiens /GRCh37.74 R883C 0.04 DELETERIOUS PROBABLY DAMAGING 0.995
rs143010673 Homo_sapiens /GRCh37.74 W22C 0 DELETERIOUS - -
rs143010673 Homo_sapiens /GRCh37.74 W137C 0.001 DELETERIOUS POSSIBLY DAMAGING 0.79
rs143010673 Homo_sapiens /GRCh37.74 W198C 0.002 DELETERIOUS PROBABLY DAMAGING 1
rs143554211 Homo_sapiens /GRCh37.74 R695C 0.019 DELETERIOUS - -
rs143554211 Homo_sapiens /GRCh37.74 R494C 0.02 DELETERIOUS PROBABLY DAMAGING 1
rs143554211 Homo_sapiens /GRCh37.74 R259C 0.021 DELETERIOUS PROBABLY DAMAGING 0.999
rs143554211 Homo_sapiens /GRCh37.74 R832C 0.032 DELETERIOUS PROBABLY DAMAGING 0.999
rs143554211 Homo_sapiens /GRCh37.74 R871C 0.032 DELETERIOUS PROBABLY DAMAGING 0.999
rs143554211 Homo_sapiens /GRCh37.74 R709C 0.033 DELETERIOUS PROBABLY DAMAGING 1
rs143686298 Homo_sapiens /GRCh37.74 P732T 0.022 DELETERIOUS POSSIBLY DAMAGING 0.555
rs143686298 Homo_sapiens /GRCh37.74 P771T 0.023 DELETERIOUS POSSIBLY DAMAGING 0.555
rs145103030 Homo_sapiens /GRCh37.74 R542C 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs145103030 Homo_sapiens /GRCh37.74 R880C 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs145103030 Homo_sapiens /GRCh37.74 R743C 0.001 DELETERIOUS - -
rs145103030 Homo_sapiens /GRCh37.74 R919C 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs145103030 Homo_sapiens /GRCh37.74 R757C 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs145521752 Homo_sapiens /GRCh37.74 E813A 0.006 DELETERIOUS PROBABLY DAMAGING 0.965
rs145521752 Homo_sapiens /GRCh37.74 E852A 0.006 DELETERIOUS POSSIBLY DAMAGING 0.939
rs145521752 Homo_sapiens /GRCh37.74 E690A 0.007 DELETERIOUS PROBABLY DAMAGING 1
rs145521752 Homo_sapiens /GRCh37.74 E676A 0.008 DELETERIOUS - -
rs145521752 Homo_sapiens /GRCh37.74 E475A 0.01 DELETERIOUS PROBABLY DAMAGING 0.978
rs145521752 Homo_sapiens /GRCh37.74 E240A 0.013 DELETERIOUS PROBABLY DAMAGING 1
rs147901996 Homo_sapiens /GRCh37.74 N145S 0.031 DELETERIOUS - -
rs147901996 Homo_sapiens /GRCh37.74 N106S 0.035 DELETERIOUS POSSIBLY DAMAGING 0.932
rs147901996 Homo_sapiens /GRCh37.74 N260S 0.043 DELETERIOUS POSSIBLY DAMAGING 0.719
rs148745528 Homo_sapiens /GRCh37.74 K99E 0 DELETERIOUS PROBABLY DAMAGING 1
rs148745528 Homo_sapiens /GRCh37.74 K138E 0 DELETERIOUS - -
rs148745528 Homo_sapiens /GRCh37.74 K253E 0 DELETERIOUS PROBABLY DAMAGING 1
rs148745528 Homo_sapiens /GRCh37.74 K275E 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs148745528 Homo_sapiens /GRCh37.74 K314E 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs185306467 Homo_sapiens /GRCh37.74 I21N 0.002 DELETERIOUS - -
rs185306467 Homo_sapiens /GRCh37.74 I136N 0.002 DELETERIOUS POSSIBLY DAMAGING 0.938
rs185306467 Homo_sapiens /GRCh37.74 I197N 0.002 DELETERIOUS POSSIBLY DAMAGING 0.892
rs188947672 Homo_sapiens /GRCh37.74 L706V 0.016 DELETERIOUS POSSIBLY DAMAGING 0.926
rs188947672 Homo_sapiens /GRCh37.74 L728V 0.033 DELETERIOUS POSSIBLY DAMAGING 0.926
rs188947672 Homo_sapiens /GRCh37.74 L591V 0.036 DELETERIOUS - -
rs188947672 Homo_sapiens /GRCh37.74 L155V 0.206 TOLERATED POSSIBLY DAMAGING 0.944
rs189785572 Homo_sapiens /GRCh37.74 A501S 0.024 DELETERIOUS PROBABLY DAMAGING 0.987
rs189785572 Homo_sapiens /GRCh37.74 A386S 0.03 DELETERIOUS - -
rs193252599 Homo_sapiens /GRCh37.74 E168K 0.017 DELETERIOUS POSSIBLY DAMAGING 0.868
rs193252599 Homo_sapiens /GRCh37.74 E604K 0.039 DELETERIOUS - -
rs199892342 Homo_sapiens /GRCh37.74 V671A 0.029 DELETERIOUS - -
rs200172149 Homo_sapiens /GRCh37.74 T202A 0.035 DELETERIOUS POSSIBLY DAMAGING 0.604
rs200244068 Homo_sapiens /GRCh37.74 D106G 0.005 DELETERIOUS POSSIBLY DAMAGING 0.787
rs200244068 Homo_sapiens /GRCh37.74 D167G 0.006 DELETERIOUS POSSIBLY DAMAGING 0.885
rs200395679 Homo_sapiens /GRCh37.74 A104T 0.006 DELETERIOUS PROBABLY DAMAGING 0.997
rs200919195 Homo_sapiens /GRCh37.74 Y195F 0 DELETERIOUS POSSIBLY DAMAGING 0.782
rs201944922 Homo_sapiens /GRCh37.74 L4S 0 DELETERIOUS PROBABLY DAMAGING 1
rs368282144 Homo_sapiens /GRCh37.74 P299A 0 DELETERIOUS PROBABLY DAMAGING 0.997
rs368282144 Homo_sapiens /GRCh37.74 P338A 0 DELETERIOUS - -
rs368282144 Homo_sapiens /GRCh37.74 P453A 0 DELETERIOUS PROBABLY DAMAGING 1
rs368282144 Homo_sapiens /GRCh37.74 P514A 0 DELETERIOUS PROBABLY DAMAGING 0.995
rs368282144 Homo_sapiens /GRCh37.74 P475A 0.012 DELETERIOUS PROBABLY DAMAGING 0.995
rs369226504 Homo_sapiens /GRCh37.74 T202R 0.004 DELETERIOUS PROBABLY DAMAGING 0.988
rs369226504 Homo_sapiens /GRCh37.74 T437R 0.01 DELETERIOUS POSSIBLY DAMAGING 0.82
rs369226504 Homo_sapiens /GRCh37.74 T775R 0.011 DELETERIOUS PROBABLY DAMAGING 0.997
rs369226504 Homo_sapiens /GRCh37.74 T638R 0.012 DELETERIOUS PROBABLY DAMAGING 0.999
rs369226504 Homo_sapiens /GRCh37.74 T814R 0.012 DELETERIOUS PROBABLY DAMAGING 0.994
rs369226504 Homo_sapiens /GRCh37.74 T652R 0.013 DELETERIOUS POSSIBLY DAMAGING 0.956
rs369814333 Homo_sapiens /GRCh37.74 N81I 0.026 DELETERIOUS POSSIBLY DAMAGING 0.73
rs369814333 Homo_sapiens /GRCh37.74 N517I 0.046 DELETERIOUS - -
rs369909997 Homo_sapiens /GRCh37.74 N228D 0.049 DELETERIOUS POSSIBLY DAMAGING 0.925
rs370084230 Homo_sapiens /GRCh37.74 R10Q 0.008 DELETERIOUS PROBABLY DAMAGING 1
rs370300640 Homo_sapiens /GRCh37.74 G91S 0 DELETERIOUS PROBABLY DAMAGING 1
rs370578519 Homo_sapiens /GRCh37.74 P661L 0.004 DELETERIOUS PROBABLY DAMAGING 0.979
rs370578519 Homo_sapiens /GRCh37.74 P524L 0.004 DELETERIOUS PROBABLY DAMAGING 0.979
rs370578519 Homo_sapiens /GRCh37.74 P700L 0.004 DELETERIOUS POSSIBLY DAMAGING 0.945
rs370578519 Homo_sapiens /GRCh37.74 P639L 0.009 DELETERIOUS PROBABLY DAMAGING 0.989
rs370668897 Homo_sapiens /GRCh37.74 K51T 0.021 DELETERIOUS PROBABLY DAMAGING 0.97
rs371745827 Homo_sapiens /GRCh37.74 R435C 0 DELETERIOUS PROBABLY DAMAGING 1
rs371745827 Homo_sapiens /GRCh37.74 R773C 0 DELETERIOUS PROBABLY DAMAGING 1
rs371745827 Homo_sapiens /GRCh37.74 R636C 0 DELETERIOUS - -
rs371745827 Homo_sapiens /GRCh37.74 R812C 0 DELETERIOUS PROBABLY DAMAGING 1
rs371745827 Homo_sapiens /GRCh37.74 R650C 0 DELETERIOUS PROBABLY DAMAGING 1
rs371745827 Homo_sapiens /GRCh37.74 R200C 0 DELETERIOUS PROBABLY DAMAGING  1
rs371999153 Homo_sapiens /GRCh37.74 W49C 0.002 DELETERIOUS PROBABLY DAMAGING 1
rs372752293 Homo_sapiens /GRCh37.74 T110R 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs372752293 Homo_sapiens /GRCh37.74 T49R 0.001 DELETERIOUS PROBABLY DAMAGING 1
rs374222815 Homo_sapiens /GRCh37.74 V505M 0 DELETERIOUS PROBABLY DAMAGING 1
rs374222815 Homo_sapiens /GRCh37.74 V706M 0 DELETERIOUS PROBABLY DAMAGING 1
rs374222815 Homo_sapiens /GRCh37.74 V843M 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs374222815 Homo_sapiens /GRCh37.74 V882M 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs374222815 Homo_sapiens /GRCh37.74 V720M 0.004 DELETERIOUS PROBABLY DAMAGING 1
rs374879205 Homo_sapiens /GRCh37.74 P512A 0 DELETERIOUS PROBABLY DAMAGING 0.997
rs374879205 Homo_sapiens /GRCh37.74 P713A 0 DELETERIOUS PROBABLY DAMAGING 1
rs374879205 Homo_sapiens /GRCh37.74 P850A 0.015 DELETERIOUS PROBABLY DAMAGING 1
rs374879205 Homo_sapiens /GRCh37.74 P889A 0.015 DELETERIOUS PROBABLY DAMAGING 1
rs374879205 Homo_sapiens /GRCh37.74 P727A 0.016 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R435L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R773L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R636L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R812L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R650L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375020232 Homo_sapiens /GRCh37.74 R200L 0 DELETERIOUS PROBABLY DAMAGING 1
rs375164425 Homo_sapiens /GRCh37.74 I57V 0 DELETERIOUS POSSIBLY DAMAGING 0.926
rs375164425 Homo_sapiens /GRCh37.74 I96V 0 DELETERIOUS PROBABLY DAMAGING 1
rs375553851 Homo_sapiens /GRCh37.74 N703H 0.005 DELETERIOUS PROBABLY DAMAGING 1
rs375553851 Homo_sapiens /GRCh37.74 N152H 0.008 DELETERIOUS PROBABLY DAMAGING 0.988
rs375553851 Homo_sapiens /GRCh37.74 N588H 0.021 DELETERIOUS PROBABLY DAMAGING 0.997
rs375553851 Homo_sapiens /GRCh37.74 N725H 0.022 DELETERIOUS PROBABLY DAMAGING 0.997
rs375553851 Homo_sapiens /GRCh37.74 N764H 0.022 DELETERIOUS PROBABLY DAMAGING 0.996
rs375640863 Homo_sapiens /GRCh37.74 D435G 0.004 DELETERIOUS PROBABLY DAMAGING 0.998
rs375640863 Homo_sapiens /GRCh37.74 D281G 0.005 DELETERIOUS PROBABLY DAMAGING 0.992
rs375640863 Homo_sapiens /GRCh37.74 D320G 0.005 DELETERIOUS PROBABLY DAMAGING 0.998
rs375640863 Homo_sapiens /GRCh37.74 D457G 0.024 DELETERIOUS PROBABLY DAMAGING 0.985
rs377024581 Homo_sapiens /GRCh37.74 D56G 0 DELETERIOUS PROBABLY DAMAGING 1
rs377266054 Homo_sapiens /GRCh37.74 E511V 0.038 DELETERIOUS PROBABLY DAMAGING 0.998
rs377266054 Homo_sapiens /GRCh37.74 E626V 0.045 DELETERIOUS PROBABLY DAMAGING 0.999
rs377603311 Homo_sapiens /GRCh37.74 R844H 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs377603311 Homo_sapiens /GRCh37.74 R883H 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs377603311 Homo_sapiens /GRCh37.74 R721H 0.003 DELETERIOUS PROBABLY DAMAGING 1
rs377603311 Homo_sapiens /GRCh37.74 R707H 0.005 DELETERIOUS PROBABLY DAMAGING 1
rs377603311 Homo_sapiens /GRCh37.74 R506H 0.007 DELETERIOUS PROBABLY DAMAGING 1

Table 2: Illustrate SNPs predictions results by SIFT and polyphen-2 prediction tools.

Polyphen-2

The Polyphen-2 results showed 85 nsSNPs out of 143 nsSNPs as probably damaging, while 27 nsSNPs showed possibly damaging with16 nsSNPs that showed no results; they are (rs1145232/ rs111254723/ rs143010673/ rs143554211/ rs145103030/ rs145521752/ rs147901996 / rs148745528 / rs185306467/ rs188947672/ rs189785572/ rs193252599/ rs199892342/ rs368282144/ rs369226504/ rs369814333/ rs370578519/ rs371745827/ rs374222815/ rs374879205/ rs375020232/ rs375164425/ rs375553851/ rs375640863/ rs377266054/ rs377603311 at the following positions: G325R, Y751C, R721C, W22C, R695C, R743C, E676A, N145S, K138E, I21N, L591V, A386S, E604K, V671A, P338A, T638R, N517I, P524L, R636C, V706M, P713A, R636L, I96V, N588H, D320G, E511V, R707H, with ENSP00000404492 protein ID ); may be due to some sequence problems or even the software and 15 nsSNPs that were considered benign which was excluded from this study (Table 2).

I Mutant suit

According to I mutant suite-3 results I found 103 snSNPs showed decreased in protein functionality within these 103 snSNPs; 14 snSNPs were considered benign by polyphen-2 and should be excluded from this study in addition 14 snSNPs showed increased in protein functionality while 26 snSNPs were not showed any results (Table 3).

SNP Organism Amino Acid Change WT MT DDG RI I Mutant Result
rs1145232 Homo_sapiens /GRCh37.74 G286R G R -0.71 7 Decrease
rs1145232 Homo_sapiens /GRCh37.74 G325R          
rs1145232 Homo_sapiens /GRCh37.74 G440R G R -0.71 7 Decrease
rs1145232 Homo_sapiens /GRCh37.74 G501R G R -0.32 2 Decrease
rs1145232 Homo_sapiens /GRCh37.74 G462R G R -0.71 7 Decrease
rs5742973 Homo_sapiens /GRCh37.74 E27Q E Q -0.86 9 Decrease
rs56309301 Homo_sapiens /GRCh37.74 N243T N T 0.25 3 Increase
rs61756360 Homo_sapiens /GRCh37.74 T75I T I -0.35 2 Decrease
rs111254723 Homo_sapiens /GRCh37.74 Y550C Y C -0.95 0 Increase
rs111254723 Homo_sapiens /GRCh37.74 Y751C - - - - -
rs111254723 Homo_sapiens /GRCh37.74 Y888C Y C -0.95 0 Increase
rs111254723 Homo_sapiens /GRCh37.74 Y927C Y C -0.95 0 Increase
rs142159998 Homo_sapiens /GRCh37.74 R721C R C -1.02 5 Decrease
rs142159998 Homo_sapiens /GRCh37.74 R844C R C -1.02 5 Decrease
rs142159998 Homo_sapiens /GRCh37.74 R883C R C -1.02 5 Decrease
rs143010673 Homo_sapiens /GRCh37.74 W22C - - - - -
rs143010673 Homo_sapiens /GRCh37.74 W137C W C -1.53 8 Decrease
rs143010673 Homo_sapiens /GRCh37.74 W198C W C -1.53 8 Decrease
rs143554211 Homo_sapiens /GRCh37.74 R695C - - - - -
rs143554211 Homo_sapiens /GRCh37.74 R494C R C -1.06 5 Decrease
rs143554211 Homo_sapiens /GRCh37.74 R259C R C -1.09 6 Decrease
rs143554211 Homo_sapiens /GRCh37.74 R832C R C -1.06 5 Decrease
rs143554211 Homo_sapiens /GRCh37.74 R871C R C -1.06 5 Decrease
rs143554211 Homo_sapiens /GRCh37.74 R709C R C -1.06 5 Decrease
rs143686298 Homo_sapiens /GRCh37.74 P732T P T -0.83 6 Decrease
rs143686298 Homo_sapiens /GRCh37.74 P771T P T -0.83 6 Decrease
rs145103030 Homo_sapiens /GRCh37.74 R542C R C -0.97 4 Decrease
rs145103030 Homo_sapiens /GRCh37.74 R880C R C -0.97 4 Decrease
rs145103030 Homo_sapiens /GRCh37.74 R743C - - - - -
rs145103030 Homo_sapiens /GRCh37.74 R919C R C -0.97 4 Decrease
rs145103030 Homo_sapiens /GRCh37.74 R757C R C -0.97 4 Decrease
rs145521752 Homo_sapiens /GRCh37.74 E813A E A -0.67 6 Decrease
rs145521752 Homo_sapiens /GRCh37.74 E852A E A -0.67 6 Decrease
rs145521752 Homo_sapiens /GRCh37.74 E690A E A -0.67 6 Decrease
rs145521752 Homo_sapiens /GRCh37.74 E676A - - - - -
rs145521752 Homo_sapiens /GRCh37.74 E475A E A -0.67 6 Decrease
rs145521752 Homo_sapiens /GRCh37.74 E240A E A -0.67 6 Decrease
rs147901996 Homo_sapiens /GRCh37.74 N145S - - - - -
rs147901996 Homo_sapiens /GRCh37.74 N106S N S -0.24 6 Decrease
rs147901996 Homo_sapiens /GRCh37.74 N260S N S -0.24 6 Decrease
rs148745528 Homo_sapiens /GRCh37.74 K99E K E -0.19 1 Increase
rs148745528 Homo_sapiens /GRCh37.74 K138E - - - - -
rs148745528 Homo_sapiens /GRCh37.74 K253E K E -0.19 1 Increase
rs148745528 Homo_sapiens /GRCh37.74 K275E K E -0.19 1 Increase
rs148745528 Homo_sapiens /GRCh37.74 K314E K E -0.19 1 Increase
rs185306467 Homo_sapiens /GRCh37.74 I21N - - - - -
rs185306467 Homo_sapiens /GRCh37.74 I136N I N -1.84 6 Decrease
rs185306467 Homo_sapiens /GRCh37.74 I197N I N -1.84 6 Decrease
rs188947672 Homo_sapiens /GRCh37.74 L706V L V -1.48 7 Decrease
rs188947672 Homo_sapiens /GRCh37.74 L728V L V -1.47 7 Decrease
rs188947672 Homo_sapiens /GRCh37.74 L591V          
rs188947672 Homo_sapiens /GRCh37.74 L155V L V -1.47 7 Decrease
rs189785572 Homo_sapiens /GRCh37.74 A501S A S -1.02 9 Decrease
rs189785572 Homo_sapiens /GRCh37.74 A386S          
rs193252599 Homo_sapiens /GRCh37.74 E168K E K -0.6 6 Decrease
rs193252599 Homo_sapiens /GRCh37.74 E604K          
rs199892342 Homo_sapiens /GRCh37.74 V671A          
rs200172149 Homo_sapiens /GRCh37.74 T202A T A -1.69 9 Decrease
rs200244068 Homo_sapiens /GRCh37.74 D106G D G -0.75 5 Decrease
rs200244068 Homo_sapiens /GRCh37.74 D167G D G -0.75 5 Decrease
rs200395679 Homo_sapiens /GRCh37.74 A104T A T -0.56 5 Decrease
rs200919195 Homo_sapiens /GRCh37.74 Y195F Y F -0.87 7 Decrease
rs201944922 Homo_sapiens /GRCh37.74 L4S L S -2.31 9 Decrease
rs368282144 Homo_sapiens /GRCh37.74 P299A P A -1.53 8 Decrease
rs368282144 Homo_sapiens /GRCh37.74 P338A          
rs368282144 Homo_sapiens /GRCh37.74 P453A P A -1.53 8 Decrease
rs368282144 Homo_sapiens /GRCh37.74 P514A P A -1.53 8 Decrease
rs368282144 Homo_sapiens /GRCh37.74 P475A P A -1.53 8 Decrease
rs369226504 Homo_sapiens /GRCh37.74 T202R T R -0.75 6 Decrease
rs369226504 Homo_sapiens /GRCh37.74 T437R T R -0.75 6 Decrease
rs369226504 Homo_sapiens /GRCh37.74 T775R T R -0.75 6 Decrease
rs369226504 Homo_sapiens /GRCh37.74 T638R          
rs369226504 Homo_sapiens /GRCh37.74 T814R T R -0.75 6 Decrease
rs369226504 Homo_sapiens /GRCh37.74 T652R T R -0.75 6 Decrease
rs369814333 Homo_sapiens /GRCh37.74 N81I N I 0.86 5 Increase
rs369814333 Homo_sapiens /GRCh37.74 N517I          
rs369909997 Homo_sapiens /GRCh37.74 N228D N D -0.47 7 Decrease
rs370084230 Homo_sapiens /GRCh37.74 R10Q R Q -0.76 5 Decrease
rs370300640 Homo_sapiens /GRCh37.74 G91S G S -1.19 7 Decrease
rs370578519 Homo_sapiens /GRCh37.74 P661L P L 0.46 2 Increase
rs370578519 Homo_sapiens /GRCh37.74 P524L - - - - -
rs370578519 Homo_sapiens /GRCh37.74 P700L P L -0.46 2 Increase
rs370578519 Homo_sapiens /GRCh37.74 P639L P L -0.46 2 Increase
rs370668897 Homo_sapiens /GRCh37.74 K51T K T -0.54 3 Decrease
rs371745827 Homo_sapiens /GRCh37.74 R435C R C -1.15 3 Decrease
rs371745827 Homo_sapiens /GRCh37.74 R773C R C -1.15 3 Decrease
rs371745827 Homo_sapiens /GRCh37.74 R636C - - - - -
rs371745827 Homo_sapiens /GRCh37.74 R812C R C -1.15 3 Decrease
rs371745827 Homo_sapiens /GRCh37.74 R650C R C -1.15 3 Decrease
rs371745827 Homo_sapiens /GRCh37.74 R200C R C -1.15 3 Decrease
rs371999153 Homo_sapiens /GRCh37.74 W49C W C -1.62 8 Decrease
rs372752293 Homo_sapiens /GRCh37.74 T110R T R -0.46 4 Decrease
rs372752293 Homo_sapiens /GRCh37.74 T49R T R -0.64 3 Decrease
rs374222815 Homo_sapiens /GRCh37.74 V505M V M -1.32 8 Decrease
rs374222815 Homo_sapiens /GRCh37.74 V706M          
rs374222815 Homo_sapiens /GRCh37.74 V843M V M -1.32 8 Decrease
rs374222815 Homo_sapiens /GRCh37.74 V882M V M -1.32 8 Decrease
rs374222815 Homo_sapiens /GRCh37.74 V720M V M -1.32 8 Decrease
rs374879205 Homo_sapiens /GRCh37.74 P512A P A -1.27 6 Decrease
rs374879205 Homo_sapiens /GRCh37.74 P713A - - - - -
rs374879205 Homo_sapiens /GRCh37.74 P850A P A -1.27 6 Decrease
rs374879205 Homo_sapiens /GRCh37.74 P889A P A -1.27 6 Decrease
rs374879205 Homo_sapiens /GRCh37.74 P727A P A -1.27 6 Decrease
rs375020232 Homo_sapiens /GRCh37.74 R435L R L -0.7 8 Decrease
rs375020232 Homo_sapiens /GRCh37.74 R773L R L -0.7 8 Decrease
rs375020232 Homo_sapiens /GRCh37.74 R636L - - - - -
rs375020232 Homo_sapiens /GRCh37.74 R812L R L -0.7 8 Decrease
rs375020232 Homo_sapiens /GRCh37.74 R650L R L -0.7 8 Decrease
rs375020232 Homo_sapiens /GRCh37.74 R200L R L -0.7 8 Decrease
rs375164425 Homo_sapiens /GRCh37.74 I57V I V -1.17 8 Decrease
rs375164425 Homo_sapiens /GRCh37.74 I96V - - - - -
rs375553851 Homo_sapiens /GRCh37.74 N703H N H -0.45 6 Decrease
rs375553851 Homo_sapiens /GRCh37.74 N152H N H -0.45 6 Decrease
rs375553851 Homo_sapiens /GRCh37.74 N588H - - - - -
rs375553851 Homo_sapiens /GRCh37.74 N725H N H -0.45 6 Decrease
rs375553851 Homo_sapiens /GRCh37.74 N764H N H -0.45 6 Decrease
rs375640863 Homo_sapiens /GRCh37.74 D435G D G -1.22 1 Decrease
rs375640863 Homo_sapiens /GRCh37.74 D281G D G -1.22 1 Decrease
rs375640863 Homo_sapiens /GRCh37.74 D320G - - - - -
rs375640863 Homo_sapiens /GRCh37.74 D457G D G -1.22 1 Decrease
rs377024581 Homo_sapiens /GRCh37.74 D56G D G -1.27 3 Decrease
rs377266054 Homo_sapiens /GRCh37.74 E511V - - - - -
rs377266054 Homo_sapiens /GRCh37.74 E626V E V 0.32 8 Increase
rs377603311 Homo_sapiens /GRCh37.74 R844H R H -1.43 9 Decrease
rs377603311 Homo_sapiens /GRCh37.74 R883H R H -1.43 9 Decrease
rs377603311 Homo_sapiens /GRCh37.74 R721H R H -1.43 9 Decrease
rs377603311 Homo_sapiens /GRCh37.74 R707H - - - - -
rs377603311 Homo_sapiens /GRCh37.74 R506H R H -1.43 9 Decrease

Table 3: Illustrate Imutant suite 3 results.

SNPs and GO

According to SNPs & GO prediction I showed the following results:-

PhD-SNP prediction results showed 70 snSNPs predicted as disease in addition to other 9 nSNPs that were excluded due to they gave benign by Polyphen-2, 32 nSNPs considered neutral in addition to other 6 snSNPs which was considered benign according to Polyphen-2 and excluded from this study too while 26 snSNPs that showed no prediction results.

SNPS & GO prediction showed 53 snSNPs that predicted as disease and 49 snSNPs as neutral in addition to 15 snSNPs that considered benign by Polyphen-2 while 26 snSNPs that did not showed any prediction results; both benign and non-prediction snSNPs they are excluded from this study.

Meta-SNP

According to Meta-SNP prediction I showed the following results:-

PhD-SNP showed 69 snSNPs considered as disease in addition to other 9 nSNPs that were excluded due to they gave benign by Polyphen-2, 32 snSNPs were considered neutral in addition to other 6 nSNPs that were excluded due to they gave benign by Polyphen-2 while 26 snSNPs showed no predictions result, both benign and nonprediction snSNPs they are excluded from this study.

SIFT results showed 78 snSNPs as disease in addition to other 10 snSNPs that were excluded due to they predict benign by Polyphen-2, 22 snSNPs showed neutral in addition to other 5 snSNPs that where considered benign by Polyphen-2, 2 snSNPs showed NA and 26 snSNPs showed no results both benign and non-prediction snSNPs they are excluded from this study.

SNAP prediction illustrate 76 snSNPs as disease in addition to other 8snSNPs that excluded considered by Polyphen-2 due to benign predictions, 26 snSNPs they are neutral with 7snSNPs as benign by polyphen-2 and 26 snSNPs without any information.

Meta- SNP prediction showed 68 snSNPs as disease disease in addition to other 7 snSNPs that considered benign by polyphen-2 and exclude from this study; 34 snSNPs predicted as neutral disease in addition to other 8 snSNPs which was considered benign by – polyphen-2 and 26 snSNPs without any prediction information, those without prediction with those considered benign by polyphen-2 are excluded from this study too (Table 4).

SNP PhD-SNP prediction  PhD-SNP IR  PhD-SNP probability  SNPS & GO prediction  SNPS & GO IR SNPS & GO probability Meta- SNP prediction Meta- SNP Probability Meta- SNP IR
rs1145232 Disease 4 0.69 Neutral 0 0.496 Disease 0.697 4
rs1145232                  
rs1145232 Disease 6 0.79 Disease 2 0.578 Disease 0.733 5
rs1145232 Disease 6 0.782 Disease 4 0.703 Disease 0.75 5
rs1145232 Disease 6 0.783 Disease 4 0.703 Disease 0.764 5
rs5742973 Disease 4 0.718 Neutral 0 0.484 Disease 0.698 4
rs56309301 Neutral 6 0.2 Neutral 9 0.063 Neutral 0.163 7
rs61756360 Disease 7 0.831 Disease 5 0.733 Disease 0.703 4
rs111254723 Neutral 5 0.272 Neutral 8 0.083 Neutral 0.174 7
rs111254723                  
rs111254723 Neutral 2 0.389 Neutral 7 0.156 Neutral 0.234 5
rs111254723 Neutral 1 0.454 Neutral 6 0.183 Neutral 0.304 4
rs142159998 Disease 5 0.729 Disease 5 0.75 Disease 0.683 4
rs142159998 Disease 5 0.728 Disease 5 0.749 Disease 0.686 4
rs142159998 Disease 5 0.728 Disease 5 0.749 Disease 0.686 4
rs143010673                  
rs143010673 Neutral 2 0.386 Neutral 2 0.417 Disease 0.537 1
rs143010673 Neutral 2 0.386 Neutral 1 0.441 Disease 0.703 4
rs143554211                  
rs143554211 Disease 3 0.638 Neutral 2 0.379 Neutral 0.457 1
rs143554211 Neutral 0 0.484 Neutral 4 0.281 Neutral 0.448 1
rs143554211 Disease 6 0.81 Disease 2 0.625 Disease 0.649 3
rs143554211 Disease 6 0.812 Disease 3 0.626 Disease 0.645 3
rs143554211 Disease 6 0.814 Disease 3 0.628 Disease 0.651 3
rs143686298 Neutral 1 0.457 Neutral 7 0.155 Neutral 0.259 5
rs143686298 Neutral 1 0.472 Neutral 7 0.162 Neutral 0.322 4
rs145103030 Disease 6 0.778 Neutral 1 0.438 Disease 0.648 3
rs145103030 Disease 7 0.841 Disease 3 0.661 Disease 0.7 4
rs145103030                  
rs145103030 Disease 7 0.842 Disease 3 0.672 Disease 0.701 4
rs145103030 Disease 7 0.843 Disease 4 0.688 Disease 0.7 4
rs145521752 Disease 5 0.757 Disease 4 0.687 Disease 0.603 2
rs145521752 Disease 5 0.76 Disease 4 0.687 Disease 0.643 3
rs145521752 Disease 5 0.761 Disease 4 0.688 Disease 0.65 3
rs145521752                  
rs145521752 Disease 3 0.673 Disease 1 0.53 Disease 0.625 3
rs145521752 Disease 4 0.688 Disease 1 0.547 Disease 0.628 3
rs147901996                  
rs147901996 Neutral 5 0.253 5 0.253 Neutral 8 0.088 Neutral 0.307 4
rs147901996 Neutral 7 0.158 Neutral 9 0.06 Neutral 0.244 5
rs148745528 Disease 2 0.612 2 0.612 Disease 5 0.765 Disease 0.681 4
rs148745528                  
rs148745528 Disease 5 0.729 Disease 6 0.811 Disease 0.824 6
rs148745528 Disease 6 0.803 Disease 7 0.861 Disease 0.861 7
rs148745528 Disease 6 0.811 Disease 7 0.859 Disease 0.872 7
rs185306467                  
rs185306467 Disease 4 0.693 Disease 2 0.619 Disease 0.576 2
rs185306467 Neutral 1 0.469 Neutral 1 0.441 Disease 0.619 2
rs188947672 Neutral 6 0.194 Neutral 8 0.075 Neutral 0.221 6
rs188947672 Neutral 1 0.445 Neutral 6 0.214 Neutral 0.259 5
rs188947672                  
rs188947672 Neutral 7 0.148 Neutral 9 0.056 Neutral 0.146 7
rs189785572 Disease 7 0.835 Disease 2 0.615 Disease 0.683 4
rs189785572                  
rs193252599 Neutral 0 0.478 Neutral 4 0.302 Neutral 0.4 2
rs193252599                  
rs199892342                  
rs200172149 Neutral 1 0.433 Neutral 6 0.178 Neutral 0.237 5
rs200244068 Neutral 5 0.255 Neutral 8 0.11 Neutral 0.389 2
rs200244068 Neutral 2 0.4 Neutral 6 0.221 Disease 0.513 0
rs200395679 Disease 3 0.638 Disease 1 0.534 Neutral 0.462 1
rs200919195 Neutral 6 0.181 Neutral 9 0.073 Neutral 0.088 8
rs201944922 Disease 0 0.503 Neutral 4 0.284 Disease 0.639 3
rs368282144 Neutral 4 0.32 Neutral 8 0.081 Neutral 0.243 5
rs368282144                  
rs368282144 Neutral 1 0.453 Neutral 8 0.109 Neutral 0.314 4
rs368282144 Disease 1 0.551 Neutral 6 0.208 Disease 0.617 2
rs368282144 Disease 1 0.551 Neutral 6 0.208 Disease 0.617 2
rs369226504 Disease 5 0.743 Disease 1 0.538 Disease 0.634 3
rs369226504 Disease 4 0.714 4 0.714 Disease 0 0.524 Disease 0.609 2
rs369226504 Disease 7 0.872 Disease 5 0.73 Disease 0.694 4
rs369226504                  
rs369226504 Disease 7 0.871 Disease 4 0.724 Disease 0.693 4
rs369226504 Disease 7 0.868 Disease 4 0.724 Disease 0.681 4
rs369814333 Neutral 3 0.369 Neutral 4 0.282 Neutral 0.227 5
rs369814333                  
rs369909997 Neutral 6 0.218 Neutral 9 0.032 Neutral 0.228 5
rs370084230 Neutral 2 0.379 Neutral 8 0.116 Neutral 0.251 5
rs370300640 Disease 7 0.866 Disease 6 0.819 Disease 0.756 5
rs370578519 Disease 4 0.719 Neutral 6 0.206 Disease 0.587 2
rs370578519                  
rs370578519 Disease 5 0.728 Neutral 6 0.219 Disease 0.586 2
rs370578519 Neutral 1 0.462 Neutral 8 0.084 Neutral 0.292 4
rs370668897 Neutral 2 0.385 Neutral 7 0.145 Neutral 0.154 7
rs371745827 Disease 4 0.687 Disease 3 0.656 Disease 0.74 5
rs371745827 Disease 6 0.819 Disease 6 0.792 Disease 0.77 5
rs371745827                  
rs371745827 Disease 6 0.819 Disease 6 0.792 Disease 0.77 5
rs371745827 Disease 6 0.819 Disease 6 0.792 Disease 0.766 5
rs371745827 Disease 3 0.671 Disease 3 0.647 Disease 0.68 4
rs371999153 Disease 8 0.898 Disease 8 0.876 Disease 0.868 7
rs372752293 Disease 7 0.852 Disease 8 0.885 Disease 0.858 7
rs372752293 Disease 8 0.882 Disease 8 0.89 Disease 0.791 6
rs374222815 Disease 2 0.624 Disease 0 0.524 Neutral 0.48 0
rs374222815                  
rs374222815 Disease 3 0.654 Disease 1 0.544 Neutral 0.471 1
rs374222815 Disease 3 0.654 Disease 1 0.544 Neutral 0.479 0
rs374222815 Disease 3 0.653 Disease 1 0.539 Neutral 0.483 0
rs374879205 Neutral 2 0.378 Neutral 7 0.142 Neutral 0.215 6
rs374879205                  
rs374879205 Disease 1 0.558 Neutral 5 0.274 Disease 0.633 3
rs374879205 Disease 1 0.569 Neutral 4 0.289 Disease 0.633 3
rs374879205 Disease 2 0.579 Neutral 4 0.304 Disease 0.633 3
rs375020232 Disease 6 0.791 Disease 4 0.701 Disease 0.676 4
rs375020232 Disease 7 0.869 Disease 6 0.821 Disease 0.732 5
rs375020232                  
rs375020232 Disease 7 0.869 Disease 6 0.82 Disease 0.734 5
rs375020232 Disease 7 0.868 Disease 6 0.82 Disease 0.707 4
rs375020232 Disease 6 0.778 Disease 4 0.692 Disease 0.71 4
rs375164425 Neutral  1 0.453 Neutral 0.268 5 0.268 Neutral 0.362 3
rs375164425                  
rs375553851 Disease 1 0.528 Neutral 0.268 5 0.25 Disease 0.582 2
rs375553851 Neutral 2 0.392 Neutral 7 0.17 Neutral 0.24 5
rs375553851                  
rs375553851 Disease 3 0.634 Neutral 1 0.436 Disease 0.607 2
rs375553851 Disease 3 0.641 Neutral 1 0.442 Disease 0.612 2
rs375640863 Disease 3 0.644 Neutral 4 0.295 Disease 0.566 1
rs375640863 Neutral 0 0.494 Neutral 6 0.218 Disease 0.566 1
rs375640863                  
rs375640863 Disease 5 0.733 Neutral 0 0.498 Disease 0.634 3
rs377024581 Disease 8 0.921 Disease 6 0.797 Disease 0.637 3
rs377266054                  
rs377266054 Neutral 2 0.405 Neutral 6 0.197 Neutral 0.262 5
rs377603311 Disease 4 0.694 Disease 4 0.708 Disease 0.606 2
rs377603311 Disease 4 0.694 Disease 4 0.708 Disease 0.606 2
rs377603311 Disease 4 0.693 Disease 4 0.709 Disease 0.577 2
rs377603311                  
rs377603311 Disease 3 0.638 Disease 2 0.58 Neutral 0.444 1

Table 4: Illustrate SNPs & GO, Meta-SNP prediction results.

Discussion

Hemophilia is one of the hematologic important disease especially type A then followed by type B and C here in Sudan we showed hemophilia in a higher numbers of population may be due to habits of relative marriage beside cost of treatment was very expensive; in this study I used in-silico methods in translation topic to detect some SNP effects on already available untested database for hemophilia B; according to those tools that I was already used such as Proven, sift, polyphen-2, I mutant suite 3, SNPs & GO and Meta- SNP prediction, I found the previous results in addition to that there are some differences between these methods results specially when trying to confirm their results with another tools, which represented in the followings; In rs56309301→N243T it represented deleterious, tolerated, neutral, neutral according to sift, sift & proven, sift in metasnp sequential, in rs111254723→(Y550C, Y888C, Y927C) represented deleterious, neutral, tolerated, disease; rs111254723→(Y751C) represented deleterious, neutral, tolerated, without sift from metasnp prediction; rs143010673→(W137C) deleterious, deleterious, damaging, neutral; rs143554211→(R695C) deleterious, neutral, damaging, without prediction; rs143554211→(R494C) deleterious, neutral, damaging, neutral; rs143554211→(R259C, R832C, R871C, R709C) deleterious, neutral, damaging, disease; rs143686298 →(P732T, P771T) deleterious, neutral, damaging, neutral; rs147901996→(N106S) deleterious, deleterious, damaging, neutral; rs148745528→(K99E) deleterious, deleterious, damaging, NA; rs148745528→(K253E) deleterious, deleterious, damaging, neutral; rs185306467→(I136N, I197N) deleterious, deleterious, damaging, neutral; rs188947672→(L706V, L728V) deleterious, neutral, damaging, disease; rs188947672→(L155V) tolerated, neutral, damaging, disease; rs189785572→( A501S, A386S) deleterious, neutral, damaging, disease/ without meta-snp prediction; rs193252599→(E168K, E604K) deleterious, neutral, tolerated/damaging, disease/ without meta-snp prediction; rs199892342→( V671A) deleterious, neutral, damaging, without meta-snp prediction; rs200172149→(T202A) deleterious, neutral, tolerated, neutral; rs200244068→(D106G, D167G) deleterious, deleterious, damaging, neutral; rs200395679→(A104T) deleterious, neutral, damaging, disease; rs200919195→(Y195F) deleterious, neutral, tolerated, neutral; rs368282144→( P299A, P453A, P338A) deleterious, deleterious, damaging, neutral/ neutral/without meta-snp prediction; rs368282144→(P514A, P475A) deleterious, deleterious, tolerated, disease; rs369226504→(T202R, T775R, T814R) deleterious, deleterious, damaging, disease; rs369226504→(T437R, T652R, T638R) deleterious, neutral, damaging, disease/ disease /without meta-snp prediction; rs369814333→(N81I, N517I) deleterious, deleterious/neutral, tolerated, neutral/ without meta-snp prediction; rs369909997→(N228D )deleterious, neutral, tolerated, neutral; rs370084230→(R10Q) deleterious, deleterious, damaging, neutral; rs370668897→(K51T )deleterious, deleterious, damaging, neutral; rs372752293→(T49R) deleterious, deleterious, damaging, neutral; rs374222815 →(V505M, V843M, V882M, V720M, V706M) deleterious, neutral, damaging, disease/ disease/ disease/ disease/ without meta-snp prediction ; rs374879205→(P512A, P713A, P850A, P889A, P727A) deleterious, deleterious, damaging, neutral /without meta-snp prediction /disease/disease/disease; rs375020232→(R200L) deleterious, deleterious, damaging, disease; rs375164425→(I57V, I96V) deleterious, neutral, tolerated, NA/ without meta-snp prediction; rs375553851→(N703H, N152H, N588H, N725H, N764H) deleterious, neutral/ deleterious/neutral/ neutral/ neutral, damaging, disease; rs375640863→(D435G, D281G, D320G, D457G) deleterious, deleterious, damaging, neutral/disease/ without meta-snp prediction/ disease; rs377266054→(E511V, E626V) deleterious, neutral, damaging, without meta-snp prediction /disease; rs377603311→(R844H, R883H, R721H, R707H, R506H) deleterious, deleterious /deleterious /neutral/deleterious /deleterious, damaging, disease/ disease/ disease/ without meta-snp prediction /disease; these represented sequential predictions for sift, sift & proven, sift in meta-snp ordinary.

PhD-SNP prediction for both SNPs & GO and Meta-snp tools showed similar prediction, in addition to some similarity or very tiny differences in PhD-SNP probability score.

SNPS & GO prediction, SNAP and Meta- SNP prediction were different in:

rs1145232→(G286R) Neutral, Disease, Disease; rs5742973→(E27Q) Neutral, Disease, Disease; rs56309301→(N243T) Neutral, Disease, Disease; rs111254723→(Y888C, Y927C) Neutral, Disease, Neutral; rs143010673→(W137C, W198C) Neutral, Neutral, Disease/ Neutral, Disease, Disease; rs143554211→(R259C) Neutral, Disease, Neutral; rs145103030→(R542C) Neutral, Disease, Disease; rs147901996→(N260S) Neutral, Disease, Neutral; rs185306467→(I136N, I197N) Disease, Neutral, Disease/ Neutral, Neutral, Disease; rs188947672→(L706V, L155V ) Neutral, Disease, Neutral; rs193252599→(E168K) Neutral, Disease, Neutral; rs200172149→(T202A) Neutral, Disease, Neutral; rs200244068→(D167G) Neutral, Neutral, Disease; rs200395679→(A104T ) Disease, Neutral, Neutral; →(L4S ) Neutral, Disease, Disease; rs368282144→(P514A, P475A) Neutral, Disease, Disease; rs370084230→(R10Q) Neutral, Disease, Neutral; rs370578519→(P661L, P700L, P639L) Neutral, Disease, Disease/ Neutral, Disease, Disease/ Neutral, Disease, Neutral; rs372752293→(T49R) Disease, Neutral, Disease; rs374222815→(V505M) Disease, Neutral, Neutral; rs374222815→(V843M,V882M,V720M) Disease, Neutral, Neutral; rs374879205→(P850A, P889A, P727A) Neutral, Disease, Disease; rs375553851→(N703H, N725H, N764H, N152H) Neutral, Disease, Disease/ Neutral, Disease, Disease/ Neutral, Disease, Disease/Neutral, Disease, Neutral; rs375640863→(D435G, D281G, D457G) Neutral, Disease, Disease; rs377266054→(E626V) Neutral, Disease, Neutral; rs377603311→(R506H) Disease, Disease, Neutral; those were not mention they are similar among the three prediction tools SNPS & GO prediction, SNAP and Meta- SNP prediction sequential.

In rs371999153→W49C was different from others SNPs because it’s responsible for ORMDL1 gene or (ORF Names: HSPC202) that located in the same chromosome position 2 (2:189782449) (https://www.ncbi.nlm.nih.gov/snp/?term=rs371999153) similar to PMS1 gene, their protein called ORM1-like protein 1 or Adoplin-1; responsible for negative regulator of sphingolipid synthesis (http://www.uniprot.org/uniprot/Q9P0S3),(https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=371999153), for Biological process is responsible for: (1) cellular sphingolipid homeostasis Source (2) ceramide metabolic process Source (3) negative regulation of ceramide biosynthetic process; they are widely expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney with expression in adult pancreas and placenta and in fetal spleen abdomen thymus while they expressed at intermediate level in pancreas, placenta and brain but low in skeletal muscle and lung, in addition they were found in subcellular location such as ERM (endoplasmic reticulum membrane) and multi-pass membrane protein.

The output of this study was explained and confirmed the damaging effect of those selected hemophilia B Snps.

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