[ensembl-dev] possible HGVSc reporting issues

[Reece Hart]

Hi-

We've compared a number of hand-curated HGVS-formatted variants against
results from VEP. Four interesting discrepancies arose in 3 transcripts
when a deletion region spanned the cds stop. In all cases, the start and
end positions were swapped in the Ensembl-generated HGVS tag. These issues
may be related to those already raised by Suresh Surampudi last week.

For example, with the VCF input (long del sequence elided):

16 89804972 CVID1002968 AC...GC A 60 PASS
cvid-type=3;CVID1002968(89804973)=del138|ref;vcf-var-code=del;id=CVID1002968;cond=FANCAfanconi;mutation-type-id=3;cvid-class=Pvar;build=GRCh37;rsid=;rnaid=NM_000135.2:c.4267_4368+36;risk-model-name=AREC;risk-model-group=qualitative-risk-model;alleles=del138,ref;curated-loc=16:89804973-89805110;full-hgvs=NM_000135.2:c.4267_4368+36del138;rel-to-dna=;hgvs-protein=;hap-region=
GT ./. ./.

We get (e!65, vep 2.3):

CVID1002968 16:89804973-89805110 - ENSG00000158805 ENST00000446326
Transcript 500B_downstream_variant - - - - - - HGNC=ZNF276
CVID1002968 16:89804973-89805110 - ENSG00000158805 ENST00000289816
Transcript 3_prime_UTR_variant 2251-2388 - - - - -
RefSeq=NM_152287.3-RefSeq_mRNA;RefSeqHGVSc=NM_152287.3:c.*319_*456delC...C;HGNC=ZNF276;CCDS=CCDS10986.1
CVID1002968 16:89804973-89805110 - ENSG00000158805 ENST00000443381
Transcript 3_prime_UTR_variant 2261-2398 - - - - -
RefSeq=NM_001113525.1-RefSeq_mRNA;RefSeqHGVSc=NM_001113525.1:c.*319_*456delC...C;HGNC=ZNF276;CCDS=CCDS45554.1
CVID1002968 16:89804973-89805110 - ENSG00000187741 ENST00000389301
Transcript
complex_change_in_transcript,3_prime_UTR_variant,coding_sequence_variant
4309-4446 - - - - -
RefSeq=NM_000135.2-RefSeq_mRNA;RefSeqHGVSc=NM_000135.2:c.*36_4267delG...G;HGVSc=ENST00000389301.2:c.*36_4267delG...G;HGNC=FANCA;CCDS=CCDS32515.1
CVID1002968 16:89804973-89805110 - ENSG00000187741 ENST00000305699
Transcript 5KB_downstream_variant - - - - - - HGNC=FANCA

Note the "c.*36_4267del" line. The CDS ends at 4368, this HGVS has end <
start.


Other examples include:

curated: NM_000135.2:c.4267_4368+36del138
vep: NM_000135.2:c.*36_4267delGCTG...

curated: NM_000135.2:c.4268_4368+37del138
vep: NM_000135.2:c.*37_4268delCTGA...

curated: NM_004992.3:c.1448_*29del43
vep: NM_004992.3:c.*29_1448delAGAGAGTTAGCTGACTTTACACGGAGCGGATTGCAAAGCAAAC

curated: NM_130839.1:c.2616_2630del15
vep: NM_130839.2:c.*11_2616delGTAAAACAAAACAAA


Thanks,
Reece
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