[ensembl-dev] Variant Effect Predictor (VariationFeature.pm) problem with $hgvs_notation

[Pontus Larsson]

Hi Michael,

This is indeed a bug in the HGVS nomenclature generation. I've committed a
fix to the CVS so if you download a new version of
the ensembl-variation/modules/Bio/EnsEMBL/Variation/VariationFeature.pm
module (from head or ensembl-branch-63 code) and replace your existing
module with it, the output should be correct. In your specific example - as
you point out - the mutation is "silent" w.r.t. the protein so the HGVS
notation should not indicate it as an insertion.

Many thanks for reporting this and apologies for any inconvenience.
/Pontus Larsson - Ensembl Variation


2011/8/4 Michael Yourshaw <myourshaw at ucla.edu>

> I get this error on some VCF files with the Variant Effect Predictor. It
> seems to be caused by an anomaly in the VariationFeature hgvs_notation code
> when an insert follows a stop codon (and maybe in other cases?).
>
> substr outside of string at
> /share/apps/myourshaw/ensembl/ensembl-variation/modules/Bio/EnsEMBL/Variation/VariationFeature.pm
> line 1675, <GEN0> line 10050.
> Use of uninitialized value in concatenation (.) or string at
> /share/apps/myourshaw/ensembl/ensembl-variation/modules/Bio/EnsEMBL/Variation/VariationFeature.pm
> line 1675, <GEN0> line 10050.
>
> An example of a VCF input line is:
> 16 84497336 . T TAGTGGA 6710.07 InDel
> AC=1;AF=0.50;AN=2;BaseQRankSum=-7.179;DP=159;FS=2.028;GC=55.61;HRun=0;HaplotypeScore=765.4756;IndelType=INS.NumRepetitions_1.EventLength_6.;MQ=153.37;MQ0=0;MQ0Fraction=0.0000;MQRankSum=5.013;Num454=0;NumOther=0;NumSLX=159;NumSOLiD=0;QD=42.20;ReadPosRankSum=-0.390;SB=-3325.82;SBD=1.32
> GT:AD:DP:GQ:PL 0/1:112,47:159:99:6710,0,4955
>
> The code in VariationFeature.pm that throws the error is:
>   $hgvs_notation->{'hgvs'} .= substr($hgvs_notation->{'ref'},0,3) .
> $hgvs_notation->{'start'} . '_' . substr($hgvs_notation->{'ref'},3,3) .
> $hgvs_notation->{'end'} . $hgvs_notation->{'type'} .
> $hgvs_notation->{'alt’};
>
> In this example, $hgvs_notation->{'ref’} is ‘X’.
>
> So substr($hgvs_notation->{'ref'},3,3) emits a warning and returns undef.
>
> Apparently this situation arises because the termination codon is being
> represented as ‘X’ instead of the 3-letter ‘Ter’
> # Replace termination codon code 'Ter' with the HGVS-preferred 'X'
> $hgvs_notation->{'alt'} =~ s/Ter|\*/X/i;
> $hgvs_notation->{'ref'} =~ s/Ter|\*/X/i;
>
> Perhaps this is merely a case of an annoying warning the needs to be
> cleaned up. Possibly, also, something may end up missing in the HGVSp
> string. In my example, this string comes out
> as ENSP00000393378.2:p.X796_[?]797insTrpLysextX3 where nothing is at the
> position indicated by [?].
>
> This example raises another question.
>
> Is it correct to  append “extX3” to the HGVSp string if what is going on
> here is an insert after the stop codon rather than a lost stop?
>
> ॐ
>
> Michael Yourshaw
> UCLA Geffen School of Medicine
> Department of Human Genetics, Nelson Lab
> 695 Charles E Young Drive S
> Gonda 5554
>
> Los Angeles CA 90095-8348 USA
>
> myourshaw at ucla.edu
>
> 970.691.8299
>
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