NMD Escape tracks on hg38

[Luis Nassar]

We are pleased to announce a new NMD Escape track on the human genome assembly (GRCh38/hg38). This track collection displays regions where premature termination codons (PTCs) are predicted to escape nonsense-mediated mRNA decay (NMD), a cellular quality control mechanism that normally degrades transcripts with premature stop codons. Identifying NMD escape regions is important for interpreting the clinical significance of truncating variants under the ACMG/AMP PVS1 criterion.

The container track includes:

• NMD escape ruleset tracks for GENCODE V49 and NCBI RefSeq transcripts, applying four rules derived from Nagy & Maquat 1998 and Lindeboom et al. 2016:
  • 50 bp rule – the entire last coding exon and the last 50 bp of the penultimate coding exon. PTCs here have no downstream exon-exon junction, or are too close to it, for NMD to be triggered.
  • No-downstream-EJC rule – transcripts with a single coding exon and no 3′UTR intron. No EJC is deposited downstream of the stop codon, so any PTC in the coding sequence escapes NMD.
  • Start-proximal 100 bp rule – the first 100 bp of coding nucleotides. PTCs here escape NMD, likely through translation re-initiation at a downstream AUG codon.
  • Long-exon rule – coding exons longer than 400 bp (excluding the last coding exon). NMD efficiency drops in very long exons because the PTC is far from the downstream exon-exon junction.
• NMDetective machine-learning prediction tracks from Lindeboom et al. 2016, providing continuous NMD efficiency scores for every possible PTC position.

We would like to thank Guido Neidhardt and Andreas Lahner for suggesting this track and providing feedback throughout its development, and the Decipher Genome Browser team for inspiring this type of visualization.