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

[Michael Yourshaw]

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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