We searched for gene sets with fewer rare pLOF variants than expected based on gene size. The gene sets with strong functional constraint included genes that encode DNA- and RNA-binding proteins, spliceosomal complexes, translation initiation machinery and RNA splicing and processing proteins (Supplementary Table 7). Genes associated with human disease in COSMIC17 (31% depletion), the GWAS catalogue18 (around 8% depletion), OMIM19 (4% depletion) and ClinVar20 (4% depletion) all contained fewer rare pLOF variants than expected (each comparison P < 10−4).
