Enhanced prediction of gene and missense rare-variant pathogenicity by joint analysis of gene burden and amino-acid residue position [article]

Adam Waring, Andrew Harper, Silvia Salatino, Christopher Kramer, Stefan Neubauer, Kate Thomson, Hugh Watkins, Martin Farrall, HCMR Investigators
2019 bioRxiv   pre-print
Although rare missense variants underlying a number of Mendelian diseases have been noted to cluster in specific regions of proteins, this information may be underutilized when evaluating the pathogenicity of a gene or variant. We introduce ClusterBurden and GAMs, two methods for rapid association testing and predictive modelling, respectively, that combine variant burden and amino-acid residue clustering, in case-control studies. We show that ClusterBurden increases statistical power to
more » ... y disease genes driven by missense variants, in simulated and experimental 34-gene panel for hypertrophic cardiomyopathy. We then demonstrate that GAMs can be used to apply the ACMG criteria PM1 and PP3 quantitatively, and resolve a wide range of pathogenicity potential amongst variants of uncertain significance. An R package is available for association testing using ClusterBurden, and a web application (Pathogenicity_by_Position) is available for missense variant risk prediction using GAMs for six sarcomeric genes. In conclusion, the inclusion of amino-acid residue positional information enhances the accuracy of gene and rare variant pathogenicity interpretation.
doi:10.1101/826164 fatcat:366d5vqkajdiditsqivyf5yhte