Fig. 3: Deep assessment of 734 predicted high-confidence (HC) loss-of-function (pLoF) variants found in 77 haploinsufficient (HI) genes in 76,215 genomes.

a Schematic of how modifying variants (black) may result in lack of a phenotype. b Filtering approach. 1KG: 1000 Genomes Project, AB: Allele balance, CH: clonal hematopoesis, MANE: Matched Annotation from NCBI and EMBL-EBI. c Variant count per HI gene colored by (also for e-g): explained (blue), uncertain (gray), unexplained (red). The number indicates unexplained variants (red). d The explanation for evading LoF in 511 of 734 (69.6%) of variants, MNV: multi-nucleotide variant, pext: per-base-expression score, tx: transcript, cons: conservation, ‘last exon 25’ and ‘SpliceAI in frame exon 25’: less than 25% protein removed; ‘AB below 25’: allele balance <25%. e Comparison of outcome in different gene sets, this set (left), heterozygous pLoF variants in autosomal recessive (AR) disease genes in gnomAD v2 (middle), all homozygous (hom) pLoF variants in gnomAD v2 (right). f Allele frequency (AF) of variants in this set by LoF curation outcome (log₁₀ scale), lower AF for unexplained (n = 137) than explained (n = 511), p = 0.0378 two-sided Student’s t-test. g The proportion of pLoF variants explained, uncertain, or unexplained within each ClinVar clinical classification category pathogenic/likely pathogenic (P/LP), uncertain significance (VUS), benign/likely benign (B/LB).