clinAnno

clinAnno is a collection of Python scripts designed to annotate genetic variants in a .vcf file. clinAnno currently provides annotations for PS1 and PM5 variants according to criteria set forth in the ACMG recommendations. The ClinVar database is used to identify previously established, pathogenic variants.

Consider the pathogenic, missense clinVar variant in AGRN:

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	985955	rs199476396	G	C	.	.	NM_198576.3(AGRN):c.5125G>C (p.Gly1709Arg)

---

A variant is annotated with PS1 when it has the same amino acid change as an established pathogenic variant, regardless of nucleotide change.

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	985955	.	G	A	.	.	PS1=18241;NM_198576.3(AGRN):c.5125G>A (p.Gly1709Arg)

Notice:
The clinVar variant results in Arg from a CGG codon
The example variant results in Arg from a AGG codon

---

A variant is annotated PM5 when "a novel missense amino acid change occurs at the same position as another pathogenic missense change".

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	985956	.	G	C	.	.	PM5=18241;NM_198576.3(AGRN):c.5126G>C (p.Gly1709Ala)

Again, notice:
The clinVar variant results in Arg from a CGG codon
The example variant results in Ala from a GCG codon

Installation

Clone on github:

git clone https://github.com/arvkevi/clinAnno.git

Requirements

1. An annotated .vcf file that contains amino acid change information according to HGVS nomenclature (p.Trp26Cys). Variant Effect Predictor

Usage

clinVar_parser.py -- parse & save clinVar

clinVar_parser.py should be executed once, before any .vcf annotations. Runtime exceeds 15 minutes.

clinAnno$ python clinVar_parser.py

It will save a snapshot of all "pathogenic" and/or "conflicting" SNVs and Indels from clinVar as a Python dictionary object (pickle file) in the current working directory.

After the initial execution of clinVar_parser.py it's uneccessary to run it again, until clinVar releases a new update, or whenever you'd like.

clinAnno.py -- .vcf annotations

The file, clinVar_obj.p should be in your repo.
Now, annotate a .vcf:
After executing clinVar_parser.py, the file clinVar_obj.p should be in your repo.

Now, annotate any .vcf (with HGVS amino acid change annotation): The example, clinvar.chr1.anno.vcf, contains chromosome 1 variants from clinVar's .vcf.

clinAnno$ python clinAnno.py --vcf_in=clinvar.chr1.anno.vcf --vcf_out=clinvar.chr1.anno.clinAnno.vcf

Processing for large .vcf files can be sped up with the --nproc parameter:

clinAnno$ python clinAnno.py --vcf_in=clinvar.chr1.anno.vcf --vcf_out=clinvar.chr1.anno.clinAnno.vcf --nproc=4

clinAnno has been tested on multi-sample and gzipped .vcf's with success.

Results

The output of clinAnno is a copy of the original .vcf with the following changes:
If no PS1 or PM5 variants are found in clinVar, the record (variant) will be unchanged.
Otherwse, the record (variant) will have either PS1=varid(s) or PM5=varid(s) prepended to the INFO field, with multiple entries separated by ;.

The first two records from the clinAnno annotated .vcf:

clinAnno$ grep -v '^##' clinvar.chr1.anno.clinAnno.vcf | head -3

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	949523	rs786201005	C	T	.	.	PS1=183381;RS=786201005;RSPOS=949523;dbSNPBuildID=144;
1	949696	rs672601345	C	CG	.	.	RS=672601345;RSPOS=949699;dbSNPBuildID=142;

The INFO field has been truncated
Notice the second variant was not annotated with either PS1= or PM5=, indicating that the variant did not meet the criteria.

The integer after PS1= is clinVar's unique variation identifier, this directs you to the variant landing page in clinVar:
http://www.ncbi.nlm.nih.gov/clinvar/variation/183381/

Citation

Richards, Sue, et al. "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology." Genetics in Medicine (2015).