Mutation severity spectrum of rare alleles in the human genome is predictive of disease type
Fig 4
Mutation severity measures based on DeepSAV identify potential disease-associated genes.
A) Mutation severity measure (GTS score) correlates with the average number of deleterious SAVs for 17,480 human genes B) Distribution of gene count among decile bins of loss-of-function constraint measure (LOEUF) for a set of genes (>3,000) with pathogenic SAVs (red bars, labeled as "path") and for the gene sets (having the same number genes) with the lowest GTS scores computed at various cutoffs of minor allele frequencies (0.0001, 0.001, 0.01 and 1). On the x axis, 0 means the first LOEUF decile [0, 0.1] (the same extrapolation applies to other numbers). C) Distribution of gene frequency among GTS deciles (MAF cutoff 0.0001) for the same gene set with known pathogenic SAVs compared to essential and nonessential gene sets. D) Distribution of protein interactions from four databases (BioGrid [123], IntAct [124], DIP [125] and HPRD [126]) integrated in PICKLE [127] for gene sets within three different mutation severity GTS score deciles (0, 0.5 and 0.9). E) Venn diagram highlights overlap among essential genes with known pathogenic variants (labeled as "Pathogenic"), essential genes with lowest loss-of-function constraint scores (LOEUF), and essential genes with lowest mutation severity measure (GTS). F) Representation of disease class associated with genes from the overlapping set of top-ranked genes by LOEUF and GTS (126 genes, not including genes with known pathogenic SAVs).