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Transcripts

The HRMDBQ prioritizes the MANE Select transcript by default. While this is the standard for variant curation, it is important to evaluate if the specific biology of a variant requires an alternative model.

Understanding MANE

Matched Annotation from NCBI and EMBL-EBI (MANE) transcripts represent exact matches between NCBI and Ensembl transcript models.

Transcript Type Description
MANE Select A single transcript per locus, representative of the relevant biology.
MANE Plus Clinical Additional transcripts for genes where "Pathogenic" (P) or "Likely Pathogenic" (LP) variants cannot be reported via the Select transcript alone.

Example: PCSK9

In Blesa et al. (2009), researchers identified a variant affecting gene expression. Depending on the transcript model, the variant's location can be interpreted in multiple ways:

  • Coding sequence
  • 5' UTR sequence
  • Upstream promoter sequence

PCSK9 and

Figure 1: Promoter and 5' Untranslated Region of the F9 gene.

Variant Specification

The variant is located on Chromosome 1: NC_000001.11:g.55039507C>A. If we wanted to represent the variant as a 5' UTR sequence we would need to choose the corresponding transcript: NM_174936.3:c.-331C>A. However, the authors interpret the major effect as a promoter variant.

Evidence Summary

Luciferase reporter analysis indicated that the c.-332C>A variant caused a 2.5-fold increase in PCSK9 promoter activity relative to wild-type. Both patients with the mutation showed higher expression compared to samples with similar LDL-C levels.

Decision: We curate this as a Promoter variant because the preponderance of evidence suggests its effect is exerted via an alteration of promoter activity.

See also