Variant Annotation

Query and interpret gene variant clinical significance from ClinVar and dbSNP databases with ACMG guideline support.

Purpose

Provide comprehensive variant annotation including:

• Clinical significance classification (Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign)
• ACMG guideline-based pathogenicity assessment
• Population allele frequencies (gnomAD, ExAC, 1000 Genomes)
• Disease and phenotype associations
• Functional predictions (SIFT, PolyPhen, CADD)

Supported Input Formats

rs80357410

NM_007294.3:c.5096G>A

NP_009225.1:p.Arg1699Gln

NC_000017.11:g.43094692G>A

chr17:43094692:G>A

BRCA1:R1699Q

Usage

Python API

from scripts.main import VariantAnnotator

# Initialize annotator
annotator = VariantAnnotator()

# Query by rsID
result = annotator.query_variant("rs80357410")

# Query by HGVS notation
result = annotator.query_variant("NM_007294.3:c.5096G>A")

# Query by genomic coordinate
result = annotator.query_variant("chr17:43094692:G>A")

# Batch query
results = annotator.batch_query(["rs80357410", "rs28897696", "rs11571658"])

Command Line

# Single variant query
python scripts/main.py --variant rs80357410

# HGVS notation
python scripts/main.py --variant "NM_007294.3:c.5096G>A"

# Genomic coordinate
python scripts/main.py --variant "chr17:43094692:G>A"

# Batch from file
python scripts/main.py --file variants.txt --output results.json

# With output format
python scripts/main.py --variant rs80357410 --format json

Output Format

{
  "variant_id": "rs80357410",
  "gene": "BRCA1",
  "chromosome": "17",
  "position": 43094692,
  "ref_allele": "G",
  "alt_allele": "A",
  "hgvs_genomic": "NC_000017.11:g.43094692G>A",
  "hgvs_cdna": "NM_007294.3:c.5096G>A",
  "hgvs_protein": "NP_009225.1:p.Arg1699Gln",
  
  "clinical_significance": {
    "clinvar": "Pathogenic",
    "acmg_classification": "Pathogenic",
    "acmg_criteria": ["PS4", "PM1", "PM2", "PP2", "PP3", "PP5"],
    "acmg_score": 13.0,
    "review_status": "criteria provided, multiple submitters, no conflicts"
  },
  
  "disease_associations": [
    {
      "disease": "Breast-ovarian cancer, familial 1",
      "medgen_id": "C2676676",
      "significance": "Pathogenic"
    }
  ],
  
  "population_frequencies": {
    "gnomAD_genome_all": 0.000008,
    "gnomAD_exome_all": 0.000012,
    "1000G_all": 0.0
  },
  
  "functional_predictions": {
    "sift": "deleterious",
    "polyphen2": "probably_damaging",
    "cadd_score": 24.5,
    "mutation_taster": "disease_causing"
  },
  
  "literature_count": 42,
  "last_evaluated": "2023-12-15",
  
  "interpretation_summary": "This variant (BRCA1 p.Arg1699Gln) is classified as Pathogenic based on ACMG guidelines. It shows strong evidence of pathogenicity including population data (extremely rare), computational predictions (deleterious), and strong clinical significance (established association with hereditary breast-ovarian cancer)."
}

ACMG Classification Criteria

The annotator implements the ACMG/AMP guidelines for variant interpretation:

Pathogenic Evidence (Score)

• PVS1 (8.0): Null variant in a gene where LOF is known mechanism
• PS1 (4.0): Same amino acid change as known pathogenic
• PS2 (4.0): De novo with confirmed paternity/maternity
• PS3 (4.0): Well-established functional studies show damaging effect
• PS4 (4.0): Prevalence in affected > controls
• PM1 (2.0): Located in critical functional domain
• PM2 (2.0): Absent from controls (MAF <0.0001)
• PM3 (2.0): AR disorder, detected in trans with pathogenic
• PM4 (2.0): Protein length changing
• PM5 (2.0): Novel missense at same position as known pathogenic
• PM6 (2.0): Assumed de novo without confirmation
• PP1 (1.0): Cosegregation with disease
• PP2 (1.0): Missense in gene with low benign rate
• PP3 (1.0): Multiple computational evidence support
• PP4 (1.0): Phenotype/patient history matches gene
• PP5 (1.0): Reputable source reports pathogenic

Benign Evidence

• BA1 (-8.0): MAF >5% in population
• BS1 (-4.0): MAF >expected for disorder
• BS2 (-4.0): Observed in healthy adult
• BS3 (-4.0): Functional studies show no damage
• BS4 (-4.0): Lack of cosegregation
• BP1 (-1.0): Missense in gene where truncating are pathogenic
• BP2 (-1.0): Observed in trans with pathogenic
• BP3 (-1.0): In-frame indel in repetitive region
• BP4 (-1.0): Multiple computational evidence benign
• BP5 (-1.0): Alternate cause found
• BP6 (-1.0): Reputable source reports benign
• BP7 (-1.0): Synonymous with no splicing impact

Classification Thresholds

Technical Difficulty: HIGH

⚠️ AI自主验收状态: 需人工检查

This skill requires:

• NCBI E-utilities API integration (ClinVar, dbSNP)
• HGVS notation parsing and validation
• VCF format handling
• ACMG guideline implementation
• Multiple prediction algorithm integration
• Complex data transformation and scoring

Data Sources

Limitations

• Requires internet connection for database queries
• NCBI API rate limits: 3 requests/second (API key increases to 10/sec)
• Some variants may not be present in ClinVar (VUS without clinical data)
• HGVS notation parsing may fail for complex variants
• Population frequencies not available for all variants
• Functional predictions are computational estimates only

References

See

references/

• ACMG guidelines publication (Richards et al. 2015)
• ClinVar documentation
• HGVS nomenclature guide
• dbSNP data dictionary
• Example variant outputs

Safety & Disclaimer

⚠️ IMPORTANT: This tool is for research and educational purposes only. Variant interpretations are computational predictions and should not be used as the sole basis for clinical decisions. Always consult certified genetic counselors and clinical laboratories for diagnostic purposes. ACMG classifications in this tool are algorithmic estimates and may differ from expert panel reviews.

Risk Assessment

Security Checklist

• No hardcoded credentials or API keys
• No unauthorized file system access (../)
• Output does not expose sensitive information
• Prompt injection protections in place
• API requests use HTTPS only
• Input validated against allowed patterns
• API timeout and retry mechanisms implemented
• Output directory restricted to workspace
• Script execution in sandboxed environment
• Error messages sanitized (no internal paths exposed)
• Dependencies audited
• No exposure of internal service architecture

Prerequisites

# Python dependencies
pip install -r requirements.txt

Evaluation Criteria

Success Metrics

• Successfully executes main functionality
• Output meets quality standards
• Handles edge cases gracefully
• Performance is acceptable

Test Cases

1. Basic Functionality: Standard input → Expected output
2. Edge Case: Invalid input → Graceful error handling
3. Performance: Large dataset → Acceptable processing time

Lifecycle Status

• Current Stage: Draft
• Next Review Date: 2026-03-06
• Known Issues: None
• Planned Improvements:
  • Performance optimization
  • Additional feature support

Parameters

--variant

--file

--output

--format

--api-key

--delay