Fix custom annotation of breakends and non-supported SVs (exact mode)

[nuno-agostinho]

ENSVAR-5610, fixes #1397

Changelog

• Custom exact matching improvements:
  • Avoid matching breakpoints with SNPs when using custom annotation in exact mode
  • Only perform this check when using custom annotation in VCF format (other formats do not contain variant type information in a standardised way)
• Bug fix: avoid skipping all subsequent SVs after skipping one
• Improvements to warning messages thrown when skipping variants:
  • Warn when skipping any non-supported SV type
  • Trim input whitespaces to improve readability of messages
  • Bug fix: avoid calling skipped_variant_msg() with ensembl-io's parser

Documentation

• Updates to public documentation: Document --custom usage for older versions of VEP (e111) public-plugins#728

Testing

Run VEP with custom annotation in exact mode containing breakends and NON_REF SVs, such as:

1   2642609        .                               G  A  .  .  .  .  .
1 2642609   nonREF  G  <NON_REF>  892  PASS  AN=6  GT  0/1
chr11   99819752        nonREF       C       <NON_REF>        892     PASS    AN=6       GT    0/1
1       713044  DUP1     C       <CN=2>  .       .       END=755966
1       713044  DUP2     C       <CN2>  .       .       END=755966
1       713044  DUP2     C       <INS:FHJDSJH>  .       .       END=755966
chr11   99819752        MantaBND:2716:0:1:0:0:0:0       C       CAACTGAG]chr11:99820576]        892     PASS    SVTYPE=BND;MATEID=MantaBND:2716:0:1:0:0:0:1;SVINSLEN=7;SVINSSEQ=AACTGAG;BND_DEPTH=266;MATE_BND_DEPTH=24;AC=3;AN=6       GT    0/1
chr11   99820576        MantaBND:2716:0:1:0:0:0:1       C       CCTCAGTT]chr11:99819752]        892     PASS    SVTYPE=BND;MATEID=MantaBND:2716:0:1:0:0:0:0;SVINSLEN=7;SVINSSEQ=CTCAGTT;BND_DEPTH=24;MATE_BND_DEPTH=266;AC=3;AN=6       GT    0/1

Run VEP using a command such as:

gnomAD=input/gnomad.genomes.v3.1.2.sites.stripped.vcf.gz
vep --i $vcf --vcf --database --custom $gnomAD,gnomAD,vcf,exact,0,AF,HN

Output should not contain custom annotation for NON_REF and breakend variants.

[nakib103]

Should we not also report skipped variant even if it is ensembl-io parser?

Suggested change

	## unsupported SV types
	if ($self->isa('Bio::EnsEMBL::VEP::Parser')) {
	$self->skipped_variant_msg("$abbrev type is not supported") unless $res;
	}
	## unsupported SV types - always use vep parser
	Bio::EnsEMBL::VEP::Parser->skipped_variant_msg("$abbrev type is not supported") unless $res;

[nuno-agostinho]

Hey Nakib! We only use ensembl-io directly for reading custom annotation: this means we will warn the user about the multiple types of variants that are skipped in custom annotation (and these can be a lot of them in some cases). Is this information useful by default or just noise?

What about if it's only printed for custom annotation if using --verbose? Something like:

Suggested change

	## unsupported SV types
	if ($self->isa('Bio::EnsEMBL::VEP::Parser')) {
	$self->skipped_variant_msg("$abbrev type is not supported") unless $res;
	}
	## unsupported SV types
	if ($self->isa('Bio::EnsEMBL::VEP::Parser') || $self->param('verbose')) {
	Bio::EnsEMBL::VEP::Parser->skipped_variant_msg("$abbrev type is not supported") unless $res;
	}

[nakib103]

This is redundant with the next check as it makes sure both are defined.

Suggested change

	# do not match if only one of the types is defined
	return 0 if defined $ref_class xor defined $vf_class;

[nuno-agostinho]

This is not redundant:

• The other check only returns 0 if both variables are defined and not equal.
• If one is defined but the other is not, then they are not equal, and should also return 0. This check is required for this condition.

[nakib103]

ah, sorry - I missed that it was an if, you can modify the next condition to have unless -

return 0 unless defined $ref_class && defined $vf_class && $ref_class eq $vf_class;

the condition can only be true if both are defined and equal.

[nakib103]

ah, sorry - I missed that it was an if, you can modify the next condition to have unless -

return 0 unless defined $ref_class && defined $vf_class && $ref_class eq $vf_class;

the condition can only be true if both are defined and equal.

[nakib103]

LOTM !~