Investigating the pathogenicity of missense spliceogenic variants using whole-genome sequencing, RNA-sequencing, and proteomics data from population and clinical research cohorts

Missense variants that disrupt RNA splicing (MSVs) and cause loss of function, notably through cryptic site activation and frameshift.

The authors integrated WGS and circulating proteomic data from around 50,000 UK Biobank participants to characterise missense spliceogenic variants (MSVs) among around 8.3 million missense variants. 2.7% of missense variants are predicted to alter splicing (SpliceAI Δ ≥ 0.2), comparable with synonymous variants (2.8%). 57% of these MSVs have benign or neutral AlphaMissense and REVEL scores, rising to 85.2% in intrinsically disordered regions, so they would be missed by protein-centric predictors. MSVs were associated with reduced circulating levels of the cognate protein, approaching the effect of predicted loss-of-function variants. Validation of 14 predicted MSVs of uncertain significance in a clinical cohort provided strong pathogenic/likely pathogenic evidence, and screening unsolved cases from the 100,000 Genomes Project identified two novel candidate diagnostic MSVs.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical message is straightforward: a missense variant called benign by AlphaMissense or REVEL should not be dismissed without checking its splicing score, especially in disordered regions. Population-scale proteomic evidence is an original functional argument, but the clinical component remains thin (14 validated variants, two candidates) and the study is a non-peer-reviewed preprint. The work argues for systematic integration of splicing predictors into missense triage in exome and genome analysis.

Analysis by Dr Thibaut Benquey