On Nucleic Acid Research, authors from Uuniversity of Kent published the varmod tool. By incorporating protein sequence and structural feature cues into the non-synonymous variant analysis, their Variant Modeller method provides clues to understanding genotype effects on phenotype, the study authors note. Their proof-of-principle analysis of 3,000 such variants suggests VarMod predicts protein function and structural effects with accuracy that's on par with that offered by the PolyPhen-2 tool.
VarMod, modelling the functional effects of non-synonymous variants
Morena Pappalardo and Mark N. Wass
Morena Pappalardo and Mark N. Wass
Abstract
Unravelling the genotype–phenotype relationship in humans remains a challenging task in genomics studies. Recent advances in sequencing technologies mean there are now thousands of sequenced human genomes, revealing millions of single nucleotide variants (SNVs). For non-synonymous SNVs present in proteins the difficulties of the problem lie in first identifying those nsSNVs that result in a functional change in the protein among the many non-functional variants and in turn linking this functional change to phenotype. Here we present VarMod (Variant Modeller) a method that utilises both protein sequence and structural features to predict nsSNVs that alter protein function. VarMod develops recent observations that functional nsSNVs are enriched at protein–protein interfaces and protein–ligand binding sites and uses these characteristics to make predictions. In benchmarking on a set of nearly 3000 nsSNVs VarMod performance is comparable to an existing state of the art method. The VarMod web server provides extensive resources to investigate the sequence and structural features associated with the predictions including visualisation of protein models and complexes via an interactive JSmol molecular viewer. VarMod is available for use at http://www.wasslab.org/varmod.
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