Integrative and accurate annotations enhance current nonsense-mediated mRNA decay rules

Variants generating premature termination codons (PTCs) are a major cause of human genetic disease, and it is crucial to accurately assess their impact. Nonsense-mediated mRNA decay (NMD) is a surveillance system that degrades mRNAs containing PTCs to prevent the production of truncated proteins. Prior studies have shown that PTC position-dependent rules are major contributors to NMD efficiency, though they leave a portion of the variability unexplained. To improve the coverage of current NMD escape rules, we used matched human genome and transcriptome data from 1086 individuals and re-evaluated NMD efficiency by considering multi-nucleotide variants (MNVs), translation status, and RNA isoform expression as part of an accurate annotation. Integrated data assessment and accurate annotation resulted in a 12.0% improvement in the explanatory power of NMD efficiency. Furthermore, we found that variants with high allele frequency or occurring in regions of low genomic conservation escape NMD due to the presence of MNVs or the absence of translation by ribosomes. Our results emphasize the importance of accurate annotation in assessing the impact of nonsense variants.