Propose additional exception

[Jianhua Zhao]

Hello,

We encountered a FANCM variant in NGS-B 2024 CAP proficiency testing. The variant is a deletion of CTTA of two CTTA repeats. By 3' rule, the nomenclature is c.4516-5_4516-2del. However the nomenclature is misleading as it shows -2 canonical acceptor splice site is impacted. In this case 5' the deletion would reflect the biological state where the canonical acceptor site -2 position is intact.

….TCTTACTTAG[GAT….

….T         CTTAG[GAT….

Due to this we propose to add a new exception to DNA/Deletion

deletions around intron/exon junctions when the splice site is not impacted when 5 primed.

Thanks for your consideration and feel free to reach out if you have any questions.

Best regards,

Jianhua

Jianhua Zhao PhD FACMG Oncology-Clinical Operations Lead Email: jianhu...@invitae.com Mobile: (215) 432-6164 www.invitae.com Invitae is now a part of Labcorp

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[Johan den Dunnen]

Dear Jianhua,

unfortunately, to answer your question correctly, essential information is missing, you do not mention the reference sequence(s) used. We assume you mean variant NC_000014.9:g.45185212_45185215del  NM_020937.2:c.4516-5_4516-2del.

For this description, indeed, the 3'rule needs to be applied and the deletion of one of two CTTA-copies from positions c.4516-9 to c.4516-2del is described as c.4516-5_4516-2del. and NOT as c.4516-9_4516-6del. Note that from deletion and duplication variant descriptions, since the 3'rule might be involved, it is not possible to deduce the exact site which is impacted by the variant. This includes especially deletions/duplication near splice sites. We therefore see no reason to change the HGVS nomenclature by adding the suggested exception.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op maandag 17 februari 2025 om 16:36:40 UTC+1 schreef jianhu...@invitae.com: