Pointed Interpretation of Clinical Variant Significance
Project description
# Picus Pointed Interpretation of Clinical Variant Significance
## Quick Install * Linux&Mac
> sudo pip3 install picus
Windows
> pip install picus
## Example Uses
Picus examples
> picus -i input.csv -o output.json
## Evidence Collection Process
### PVS1 * PVS1 null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease.
#### Status * Implemented
#### Resources * LoF genes list from intervar. https://raw.githubusercontent.com/barslmn/InterVar/master/intervardb/PVS1.LOF.genes.hg19 * Null variants defined as HIGH IMPACT by https://www.ensembl.org/info/genome/variation/prediction/predicted_data.html
#### Conditions * “gene_symbol” is in LoF gene list. * “transcript_consequence_terms” is high impact.
#### Shortcomings * LoF gene list is only predictive and may be missing some actual LoF genes. * No checks for multiexon deletion.
### PS1 * Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
#### Status * Implemented
#### Resources * Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)
#### Annotation Steps 1. Clinvar data is parsed using https://github.com/barslmn/clinvar. 2. Sample data and clinvar data is merged based on columns “CHR” and “POS”. 3. Clinvar feature columns “ALT”, “hgvsp”, and “clinical_significance” added to original annotation.
#### Conditions 1. “clinical_significance” is pathogenic. 2. Sample “hgvsp” and later added clinvar “hgvsp” changes are the same. 3. Sample “ALT” and clinvar “ALT” are different.
#### Shortcomings
### PS2 * De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
#### Status * Not Checked
#### Resources
#### Conditions
#### Shortcomings
### PS3 * Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
#### Status * Not Checked
#### Resources
#### Conditions
#### Shortcomings
### PS4 * The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
#### Status * Implemented
#### Resources * https://github.com/WGLab/InterVar/blob/master/intervardb/PS4.variants.hg19
#### Conditions 1. “id” is in id list.
#### Shortcomings 1. No idea how the source is made.
### PM1 * Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
#### Status * Planned.
#### Resources
#### Conditions
#### Shortcomings
### PM2 * Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
#### Status * Implemented
#### Resources * VEP
#### Conditions * “gnomad” less than 0.001.
#### Shortcomings
### PM3 * For recessive disorders, detected in trans with a pathogenic variant
#### Status * Not Checked
#### Resources
#### Conditions
#### Shortcomings
### PM4 * Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
#### Status * Implemented
#### Resources * VEP
#### Conditions * “transcript_consequence_terms” is “inframe_insertion”, “inframe_deletion”, or “stop_lost”.
#### Shortcomings * No checks for repeat regions.
### PM5 * Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
#### Status * Broken.
#### Resources * Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)
#### Annotation Steps 1. Clinvar data is parsed using https://github.com/barslmn/clinvar. 2. Sample data and clinvar data hgvsp columns parsed till position. 3. Synonym changes removed from clinvar data. 4. Clinvar feature columns “hgvsc”, and “clinical_significance” added to original annotation based on protein change position.
#### Conditions 1. “gnomad” less then 0.001. 2. “clinical_significance” is pathogenic. 3. “transcript_consequence_terms” is missense variant. 4. “hgvsc” of the variant and clinvar entry dont match.
#### Shortcomings
### PM6 * Assumed de novo, but without confirmation of paternity and maternity
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### PP1 * Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### PP2 * Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
#### Status * Implemented
#### Resources * Intervar
#### Conditions * “transcript_consequence_terms” is a missense variant. * “gene_symbol” is in PP2 gene list.
#### Shortcomings
### PP3 * Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
#### Status * Implemented
#### Resources * Vep
#### Conditions * “sift_score” less than 0.05 * “polyphen_score” greater than 0.908
#### Shortcomings
### PP4 * Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### PP5 * Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
#### Status * Implemented.
#### Resources * Clinvar
#### Conditions * “clinical_significance” is Pathogenic.
#### Shortcomings
### Benign
### BA1 * Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
#### Status * Implemented.
#### Resources * Vep
#### Conditions * “minor_allele_freq” is greater than 0.05
OR
“gnomad” is greater than 0.05.
#### Shortcomings
### BS1 * Allele frequency is greater than expected for disorder
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### BS2 * Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
#### Status * Planned
#### Resources * Intervar
#### Conditions
#### Shortcomings
### BS3 * Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### BS4 * Lack of segregation in affected members of a family
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### BP1 * Missense variant in a gene for which primarily truncating variants are known to cause disease
#### Status * Implemented.
#### Resources * Intervar
#### Conditions * “transcript_consequence_terms” is a missense variant. * “gene_symbol” is in BP1 gene list.
#### Shortcomings
### BP2 * Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### BP3 * In-frame deletions/insertions in a repetitive region without a known function
#### Status
#### Resources
#### Conditions
#### Shortcomings
### BP4 * Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
#### Status * Implemented
#### Resources * VEP
#### Conditions * “sift_score” greater than or equals to 0.05 * “polyphen_score” less than or equals to 0.446
#### Shortcomings
### BP5 * Variant found in a case with an alternate molecular basis for disease
#### Status * Not Checked.
#### Resources
#### Conditions
#### Shortcomings
### BP6 * Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
#### Status * Implemented
#### Resources * Clinvar
#### Conditions * “clinical_significance” is benign
#### Shortcomings
### BP7 * A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
#### Status
#### Resources
#### Conditions
#### Shortcomings
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