Representing intronic variants in VRS

[Mrinal-Thomas-Epic]

When working on representing molecular consequences from VEP in VA-spec (PR 336), we hit some friction while representing intronic variant molecular consequences. We can represent the transcript (using SequenceReference) and molecular consequence terms, but aren't able to represent intronic variant (currently returned as an HGVS by VEP, e.g. ENST00000650946.1:n.439-1599G>C)

[ahwagner]

Today we discussed initial drafts for this as part of a broader model for representing variants on any set of aligned sequences. The conceptual model draft is publicly available here.

It was noted that we will need a mechanism for describing alignment orientation in alignmentBlocks, and that we should consider scenarios where you have 1-to-many sequence alignments as commonly seen in liftover operations.

[Mrinal-Thomas-Epic]

In the meeting today, we discussed data structures to describe aligned alleles, sequence locations, and sequence references. I was wondering if its needed to provide alignments across the whole sequence reference when describing a single aligned allele. For example,

[ahwagner]

We drafted a community model at GA4GH Connect 2025:

A notable limitation of this model is the ambiguity of an offset that can occur in either orientation (from the left or the right of the mapped anchor position) which represent different mapped coordinates. This model treats these as inherently different variants; however we also provide a normalization convention that ensures a unique representation for creating a GA4GH computed digest.

In testing this model, it also became clear that there are scenarios where an ambiguous indel spanning the intron-exon boundary results in scenarios where the variant may not be discernable solely from negative / positive offset values. Therefore, the PR (#663) will be updated to reflect this with an additional (required) offsetOrientation attribute that specifies whether the coordinates are with respect to the left or right boundary of the mapped anchor position.