<div>Hi-</div><div><br></div><div>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. </div>
<div><br></div><div>For example, with the VCF input (long del sequence elided):</div><div><br></div><div>16<span style="white-space:pre-wrap"> </span>89804972<span style="white-space:pre-wrap"> </span>CVID1002968<span style="white-space:pre-wrap"> </span>AC...GC<span style="white-space:pre-wrap"> </span>A<span style="white-space:pre-wrap"> </span>60<span style="white-space:pre-wrap"> </span>PASS<span style="white-space:pre-wrap"> </span>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=<span style="white-space:pre-wrap"> </span>GT<span style="white-space:pre-wrap"> </span>./.<span style="white-space:pre-wrap"> </span>./.<br>
</div><div><br></div><div>We get (e!65, vep 2.3):</div><div><br></div><div><div>CVID1002968<span style="white-space:pre-wrap"> </span>16:89804973-89805110<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>ENSG00000158805<span style="white-space:pre-wrap"> </span>ENST00000446326<span style="white-space:pre-wrap"> </span>Transcript<span style="white-space:pre-wrap"> </span>500B_downstream_variant<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>HGNC=ZNF276</div>
<div>CVID1002968<span style="white-space:pre-wrap"> </span>16:89804973-89805110<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>ENSG00000158805<span style="white-space:pre-wrap"> </span>ENST00000289816<span style="white-space:pre-wrap"> </span>Transcript<span style="white-space:pre-wrap"> </span>3_prime_UTR_variant<span style="white-space:pre-wrap"> </span>2251-2388<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>RefSeq=NM_152287.3-RefSeq_mRNA;RefSeqHGVSc=NM_152287.3:c.*319_*456delC...C;HGNC=ZNF276;CCDS=CCDS10986.1</div>
<div>CVID1002968<span style="white-space:pre-wrap"> </span>16:89804973-89805110<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>ENSG00000158805<span style="white-space:pre-wrap"> </span>ENST00000443381<span style="white-space:pre-wrap"> </span>Transcript<span style="white-space:pre-wrap"> </span>3_prime_UTR_variant<span style="white-space:pre-wrap"> </span>2261-2398<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>RefSeq=NM_001113525.1-RefSeq_mRNA;RefSeqHGVSc=NM_001113525.1:c.*319_*456delC...C;HGNC=ZNF276;CCDS=CCDS45554.1</div>
<div>CVID1002968<span style="white-space:pre-wrap"> </span>16:89804973-89805110<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>ENSG00000187741<span style="white-space:pre-wrap"> </span>ENST00000389301<span style="white-space:pre-wrap"> </span>Transcript<span style="white-space:pre-wrap"> </span>complex_change_in_transcript,3_prime_UTR_variant,coding_sequence_variant<span style="white-space:pre-wrap"> </span>4309-4446<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>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</div>
<div>CVID1002968<span style="white-space:pre-wrap"> </span>16:89804973-89805110<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>ENSG00000187741<span style="white-space:pre-wrap"> </span>ENST00000305699<span style="white-space:pre-wrap"> </span>Transcript<span style="white-space:pre-wrap"> </span>5KB_downstream_variant<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>-<span style="white-space:pre-wrap"> </span>HGNC=FANCA</div>
</div><div><br></div><div>Note the "c.*36_4267del" line. The CDS ends at 4368, this HGVS has end < start.</div><div><br></div><div><br></div><div>Other examples include:</div><div><br></div><div>curated: NM_000135.2:c.4267_4368+36del138</div>
<div>vep: NM_000135.2:c.*36_4267delGCTG...</div><div><br></div><div>curated: NM_000135.2:c.4268_4368+37del138<br></div><div>vep: NM_000135.2:c.*37_4268delCTGA...</div><div><br></div><div>curated: NM_004992.3:c.1448_*29del43<br>
</div><div>vep: NM_004992.3:c.*29_1448delAGAGAGTTAGCTGACTTTACACGGAGCGGATTGCAAAGCAAAC</div><div><br></div><div>curated: NM_130839.1:c.2616_2630del15</div><div>vep: NM_130839.2:c.*11_2616delGTAAAACAAAACAAA</div><div><br></div>
<div><br></div><div>Thanks,</div><div>Reece</div>