Predicting the functional consequences of non-synonymous DNA sequence variants - evaluation of bioinformatics tools and development of a consensus strategy

The study of DNA sequence variation has been transformed by recent advances in DNA sequencing technologies. Determination of the functional consequences of sequence variant alleles offers potential insight as to how genotype may influence phenotype. Even within protein coding regions of the genome, establishing the consequences of variation on gene and protein function is challenging and requires substantial laboratory investigation. However, a series of bioinformatics tools have been developed to predict whether non-synonymous variants are neutral or disease-causing. In this study we evaluate the performance of nine such methods (SIFT, PolyPhen2, SNPs&GO, PhD-SNP, PANTHER, Mutation Assessor, MutPred, Condel and CAROL) and developed CoVEC (Consensus Variant Effect Classification), a tool that integrates the prediction results from four of these methods. We demonstrate that the CoVEC approach outperforms most individual methods and highlights the benefit of combining results from multiple tools.