XM_ Transcripts over NM_ in AnnotSVv3.4.4

[aledamv]

We are currently using AnnotSV v3.4.4, for the annotation of a large dataset of structural variants (SVs and CNVs), and we have encountered a recurring issue regarding transcript prioritization.

In multiple cases, we observe that AnnotSV annotates variants using XM_ (predicted RefSeq) transcripts, even when a corresponding NM_ (curated RefSeq) transcript is available and clearly more relevant-for example, the NM_ transcript either overlaps or is disrupted by the variant.

This behavior is problematic because it leads to misleading or suboptimal annotations, especially in clinical interpretation pipelines where NM_ transcripts are expected to be prioritized whenever available.

We would appreciate your insight into the following questions:

Has there been a change in transcript prioritization logic in AnnotSV v3.4.4 that might explain this behavior?
Is there a way to explicitly force AnnotSV to prioritize NM_ transcripts over XM_ when both are available? (e.g., a parameter, configuration option, or filtered transcript reference file?)

This issue did not occur in earlier versions of AnnotSV we tested, where NM_ transcripts were consistently preferred.

We are trying to determine whether this is a version-related change, a misconfiguration on our side, or due to an upstream annotation file issue.

[lgmgeo]

Hi,

Thank you for your report.

AnnotSV rules
For each gene, only a single transcript from all transcripts available for this gene is reported in the following order of preference:

• The transcript selected by the user with the "-txFile" option is reported
• The transcript with the longest overlapped CDS is reported
• If there is no difference in CDS length, the longest overlapped transcript is reported.

There have been no changes to these rules compared to the latest versions.

In multiple cases, we observe that AnnotSV annotates variants using XM_ (predicted RefSeq) transcripts, even when a corresponding NM_ (curated RefSeq) transcript is available and clearly more relevant-for example, the NM_ transcript either overlaps or is disrupted by the variant.

Indeed, by default AnnotSV does not use the gene name (XM_ or NM_) to select the reported transcript.

Has there been a change in transcript prioritization logic in AnnotSV v3.4.4 that might explain this behavior?

No

Is there a way to explicitly force AnnotSV to prioritize NM_ transcripts over XM_ when both are available? (e.g., a parameter, configuration option, or filtered transcript reference file?)

My advice is to use the -txFile option:

For this purpose, you can create and use a file with all the "NM_" genes transcripts.

This issue did not occur in earlier versions of AnnotSV we tested, where NM_ transcripts were consistently preferred.

Can you give me the previous versions that have been evaluated?
(and your command line)

Best,

Véronique