Computational protocol: Gene-Specific Function Prediction for Non-Synonymous Mutations in Monogenic Diabetes Genes

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Protocol publication

[…] Eleven methods, including PhyloP , GERP++ RS , SiPhy , SIFT , PolyPhen-2 , the likelihood ratio test (LRT) , MutationTaster , Mutation Assessor , FATHMM , RadialSVM score , and logistic regression (LR) score , were covered in the dbNSFP database , and compared in this study (). Among the 1,091 mutations involved in this analysis, 104 mutations from the genes GCK, HNF1A, HNF1B, HNF4A, and INS, are nonsense mutations, i.e. producing a pre-termination codon; two other mutations from the gene GCK replace a termination codon with an amino acid codon. For these mutations, the methods, PolyPhen-2 HDIV, PolyPhen-2 HVAR, MutationAssessor, FATHMM, Radial SVM score, LR score are not applicable to nonsense mutations or mutations assumed with highly damaging potential. Other methods, except MutationTaster, tend to have higher error rates (false negative rates, FNR), compared to the prediction of amino acid substitution mutations, i.e. SIFT FNR = 72%, GERP++ RS FNR = 40%, PhyloP FNR = 35%, SiPhy FNR = 26%, LRT FNR = 21%, and MutationTaster FNR = 3%, for the prediction of nonsense mutations. Compared with amino acid substitutions, the assessment of the functional effect of nonsense mutations tends to be less of an issue. The final analysis of this study involved 985 nonsynonymous single-nucleotide mutations. The quantitative performances of these methods were compared by the Spearman's rank correlation test and the ANOVA test using the IBM SPSS Statistics 19 software ((IBM SPSS Inc., Chicago, IL, USA). To re-define gene-specific thresholds of deleterious mutations, the receiver operator characteristic (ROC) analysis was calculated by the sensitivity and specificity values of screening series of cutoffs of each method for each gene. A redefined threshold was identified using the maximum Matthews correlation coefficient (MCC) . […]

Pipeline specifications

Software tools PHAST, GERP, SiPhy, SIFT, PolyPhen, MutationTaster, Mutationassessor, FATHMM, SPSS
Databases dbNSFP
Application Miscellaneous
Organisms Homo sapiens
Diseases Diabetes Mellitus, Diabetes Mellitus, Type 2