Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy.

GAMs represent a unified statistical modelling framework to combine burden, clustering and functional information. Hotspot models can refine maps of regional burden and hotspot+ models can be powerful predictors of variant pathogenicity. The BIN-test is a fast powerful approach to detect missense variant clustering that when combined with burden information (ClusterBurden) may enhance disease-gene discovery.