VEP Unable to process HGVS variants

Question

[Yacob]

I have a list of 60 million variants in HGVS format (ENST00000209873:c.1_3delinsGCG). I must use this format. I'm trying to run VEP offline by using the downloaded fasta file, but it keeps saying "Cannot use HGVS format in offline mode". Can someone please let me know how I should edit my command?

vep -i test.txt --format hgvs -output_file tmp.txt
--force_overwrite --dir_cache /hpc/vep/113/cache/
--cache  --dir_plugins /hpc/packages/vep/113 --assembly
GRCh38 --fasta /sc/Homo_sapiens.GRCh38.dna.primary_assembly.fa --offline

[Pierre Lindenbaum]

cross-posted https://stackoverflow.com/questions/79344552/vep-unable-to-process-hgvs-variants

[GenoMax]

Also here: https://www.reddit.com/r/bioinformatics/comments/1hxv912/vep_not_processing_hgvs_variants_offline/

Answer 1

[GenoMax]

See hgvs notations section here: https://www.ensembl.org/info/docs/tools/vep/script/vep_other.htm

Input VEP supports using HGVS notations as input. This feature is currently under development and not all HGVS notation types are supported. Notations relative to genomic (g.) or coding (c.) sequences are fully supported; protein (p.) notations are supported in limited fashion due to the complexity involved in determining the multiple possible underlying genomic sequence changes that could produce a single protein change. A warning will be given if a particular notation cannot be parsed.

By default VEP uses Ensembl transcripts as the reference for determining consequences, and hence also for HGVS notations. However, it is possible to parse HGVS notations that use RefSeq transcripts as the reference sequence by using the --refseq flag. Such notations must include the version number of the transcript e.g.

NM_080794.3:c.1001C>T

Alternative cache (for refseq) can be downloaded using instructions here: https://www.ensembl.org/info/docs/tools/vep/script/vep_cache.html