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Estimating the proportion of nonsense variants undergoing the newly described phenomenon of manufactured splice rescue.

Authors
  • Haque, Bushra1, 2
  • Cheerie, David1, 2
  • Birkadze, Saba1, 2
  • Xu, Alice Linyan2
  • Nalpathamkalam, Thomas3
  • Thiruvahindrapuram, Bhooma3
  • Walker, Susan3
  • Costain, Gregory4, 5, 6
  • 1 Program in Genetics & Genome Biology, SickKids Research Institute, Toronto, ON, Canada. , (Canada)
  • 2 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 3 The Centre for Applied Genomics (TCAG), SickKids Research Institute, Toronto, ON, Canada. , (Canada)
  • 4 Program in Genetics & Genome Biology, SickKids Research Institute, Toronto, ON, Canada. [email protected]. , (Canada)
  • 5 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected]. , (Canada)
  • 6 Division of Clinical & Metabolic Genetics, The Hospital for Sick Children (SickKids), and Department of Paediatrics, University of Toronto, Toronto, ON, Canada. [email protected]. , (Canada)
Type
Published Article
Journal
European Journal of Human Genetics
Publisher
Springer Nature
Publication Date
Feb 01, 2024
Volume
32
Issue
2
Pages
238–242
Identifiers
DOI: 10.1038/s41431-023-01495-6
PMID: 38012313
Source
Medline
Language
English
License
Unknown

Abstract

A recent report described a nonsense variant simultaneously creating a donor splice site, resulting in a truncated but functional protein. To explore the generalizability of this unique mechanism, we annotated >115,000 nonsense variants using SpliceAI. Between 0.61% (donor gain delta score >0.8, for high precision) and 2.57% (>0.2, for high sensitivity) of nonsense variants were predicted to create new donor splice sites at or upstream of the stop codon. These variants were less likely than other nonsense variants in the same genes to be classified as pathogenic/likely pathogenic in ClinVar (p < 0.001). Up to 1 in 175 nonsense variants were predicted to result in small in-frame deletions and loss-of-function evasion through this "manufactured splice rescue" mechanism. We urge caution when interpreting nonsense variants where manufactured splice rescue is a strong possibility and correlation with phenotype is challenging, as will often be the case with secondary findings and newborn genomic screening programs. © 2023. The Author(s).

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