Mutation severity spectrum of rare alleles in the human genome is predictive of disease type
Fig 5
Mutation-intolerant and mutation-tolerant genes prefer different pathways and disease types.
A) Top ranked genes with low GTS scores like ERK2 kinase (PDB 4fmq) have relatively few DeepSAV predicted deleterious variant positions (DeepSAV score > 0.75, red spheres). One of these (black sphere) is near (< 4Å) the active site (ANP substrate analog in black stick). B) Bottom ranked genes with high GTS scores like CD36 (PDB 5lgd) are tolerant to predicted deleterious mutations (DeepSAV score > 0.75, red spheres), including several positions (black spheres) lining the fatty acid (black stick) binding sites or with known pathogenic variation in platelet glycoprotein deficiency (blue spheres). C) Mutation severity spectrum of disease-associated genes in general, measured by their frequencies in GTS deciles. (PathVar–genes with pathogenic SAVs in ClinVar and UniProt, DisGeNET–genes with diseases in DisGeNET database, X-linked, Autosomal dominant, and Autosomal recessive correspond to sets of genes associated with X-linked, autosomal dominant, and autosomal recessive diseases in the Clinical Genome Database, respectively) D) Mutation severity spectrum of disease-associated genes measured by their frequencies in GTS deciles. Associated disease for each gene set is labeled above. E) Mutation severity spectrum of pathway gene sets and large paralogous gene sets measured by their frequencies in GTS deciles.