P243: Splice rescue of protein-truncating variants is associated with reduced selection pressure and attenuated disease phenotype

Human genetic variants that alter the canonical splicing sequence could result in various splicing patterns, which is challenging for variant interpretation. It will be more complex when a coding variant occurs near the canonical splice site, and thereby the protein product is possibly influenced by both the mutated codon and the altered splicing pattern. Particularly, if the altered splicing results in an in-frame splice-out of the coding variant, the deleterious effect of the variant on the protein product could presumably be ‘rescued’.