Description

The NMD escape ruleset tracks show predicted regions where a premature termination codon (PTC) or frameshift variant is likely to cause the transcript to escape nonsense-mediated decay (NMD), leading to the production of an aberrant truncated protein rather than degradation of the mRNA.

The following rules were applied to transcript annotations to define predicted NMD escape regions (Nagy et al, Trends Biochem Sci 1998 and Lindeboom et al, Nat Genet 2016):

1. 50 bp rule: The region less than 50 bp upstream of the last exon-exon junction (after splicing). Non-protein-coding 3' exons are not considered.
2. Intronless transcripts: Transcripts with a single exon. Since no EJCs are deposited on single-exon transcripts, all PTCs are predicted to escape NMD.
3. Start-proximal region: The first 100 bp of coding nucleotides. PTCs in this region do not lead to NMD, a phenomenon known as start-proximal NMD insensitivity. One proposed mechanism, supported by experimental evidence, is re-initiation of translation at a downstream AUG codon.

Non-coding transcripts (where CDS start equals CDS end) are excluded. Overlapping regions from multiple transcripts with identical coordinates and the same rule are collapsed into a single item, with the contributing transcript IDs stored as a comma-separated list.

Two versions of this track are available, based on different transcript annotation sets:

• NMD escape Gencode: Derived from GENCODE V49 transcript annotations.
• NMD escape NCBI RefSeq: Derived from NCBI RefSeq transcript annotations.

Background

NMD escape regions were predicted based on the Exon Junction Complex (EJC)-dependent model of NMD. During normal translation, EJCs are deposited at exon-exon junctions after splicing. As the ribosome translates the mRNA, it displaces each EJC it encounters. When a PTC causes the ribosome to stall prematurely, any remaining downstream EJCs recruit surveillance factors (notably UPF1) that trigger mRNA degradation via NMD.

However, if the PTC is located within approximately 50 bp upstream of the last exon-exon junction, the ribosome is close enough to the final EJC that the interaction does not trigger NMD—the transcript escapes degradation. Conversely, PTCs located more than 50–55 bp upstream of the last exon-exon junction are predicted to elicit NMD.

Display Conventions and Configuration

Regions from overlapping transcripts with the same coordinates are collapsed into a single item. The gene symbol is shown as the item name. Mouseover displays the NMD escape rule and the number of transcripts. The details page lists all contributing transcript IDs.

Items are colored by the NMD escape rule that applies:

• Red – Rule 1: Last 50 bp of the last coding exon-exon junction. A PTC here is too close to the last exon junction complex (EJC) for NMD to be triggered.
• Orange – Rule 2: Intronless (single-exon) transcript. No EJCs are deposited, so all PTCs escape NMD.
• Dark red – Rule 3: First 100 bp of coding nucleotides. PTCs in this start-proximal region are insensitive to NMD, possibly due to translation re-initiation at a downstream AUG codon.

Data Access

The data underlying this track can be explored interactively with the Table Browser or the Data Integrator. For automated analysis, the data may be queried from our REST API. Please refer to our mailing list archives for questions, or our Data Access FAQ for more information.

Credits

Thanks to Guido Neidhardt for suggesting this track at HUGO VEPTC 2025 and Andreas Lahner for feedback. Thanks to the Decipher Genome Browser team for introducing the idea of a track.

References

Kurosaki T, Popp MW, Maquat LE. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol. 2019 Jul;20(7):406-420. PMID: 30992545; PMC: PMC6855384

Lindeboom RG, Supek F, Lehner B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet. 2016 Oct;48(10):1112-8. PMID: 27618451; PMC: PMC5045715

Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998 Jun;23(6):198-9. PMID: 9644970