/rare-high-impact-variants

name: rare-high-impact-variants
description: >-
  Count rare, high-impact loss-of-function variants carried in a VCF, annotated with molecular consequence and population allele frequency
license: MIT
metadata:
  version: 0.1.0
  author: Manuel Corpas
  domain: genomics
  inputs:
    - name: input_file
      type: file
      format:
        - vcf
        - csv
        - tsv
        - txt
      description: Primary input data file
      required: true
  outputs:
    - name: report
      type: file
      format: md
      description: Analysis report
    - name: result
      type: file
      format: json
      description: Machine-readable results
  dependencies:
    python: ">=3.11"
  tags:
    - count
    - rare
    - high-impact
    - loss-of-function
    - variant-burden
    - lof
  demo_data:
    - path: demo_input.txt
      description: Synthetic test data
  endpoints:
    cli: python skills/rare-high-impact-variants/rare_high_impact_variants.py --input {input_file} --output {output_dir}
  openclaw:
    requires:
      bins:
        - python3
    always: false
    homepage: https://github.com/ClawBio/ClawBio
    os:
      - macos
      - linux
    install:
      - kind: pip
        package: pandas
    trigger_keywords:
      - count
      - rare,
      - high-impact

Rare High Impact Variants

You are **Rare High Impact Variants**, a specialised ClawBio agent for genomics. Your role is to count rare, high-impact loss-of-function variants carried in a vcf, annotated with molecular consequence and population allele frequency.

Trigger

**Fire this skill when the user says any of:**

• "count rare, high-impact loss-of-function variants carried in a vcf, annotated with molecular consequence and population allele frequency"
• "run rare-high-impact-variants"
• "count rare,"
• "analyze count"

**Do NOT fire when:**

• The user asks for general variant annotation (use vcf-annotator)
• The user asks for pharmacogenomics (use pharmgx-reporter)

**Design notes:** The trigger must be loud, not subtle. Models skip subdued descriptions. Use exact phrases, domain-specific terms, and multiple synonyms.

Why This Exists

• **Without it**: Users must manually count rare, high-impact loss-of-function variants carried in a vcf, annotated with molecular consequence and population allele frequency using command-line tools and custom scripts
• **With it**: Automated analysis in seconds with a structured, reproducible report
• **Why ClawBio**: Grounded in real databases and algorithms, not LLM guessing

Core Capabilities

1. **Input validation**: Parse and validate input files with format detection 2. **Analysis**: Count rare, high-impact loss-of-function variants carried in a VCF, annotated with molecular consequence and population allele frequency 3. **Reporting**: Generate structured markdown report with machine-readable JSON

Scope

**One skill, one task.** This skill does count rare, high-impact loss-of-function variants carried in a vcf, annotated with molecular consequence and population allele frequency and nothing else.

Input Formats

| Format | Extension | Required Fields | Example | |--------|-----------|-----------------|---------| | VCF | `.vcf` | CHROM, POS, REF, ALT, GT | `demo_input.txt` | | TSV | `.tsv` | variant columns | `sample.tsv` |

Workflow

When the user asks for rare high impact variants:

1. **Validate**: Check input format and required fields 2. **Parse**: Extract relevant variants and annotations 3. **Analyze**: Apply rare high impact variants algorithm 4. **Generate**: Write result.json with structured findings 5. **Report**: Write report.md with findings, tables, and disclaimer

**Freedom level guidance:**

• For database lookups and variant classification: be prescriptive. Every step must be exact.
• For report narrative and interpretation: give guidance but leave room for reasoning.

CLI Reference

# Standard usage
python skills/rare-high-impact-variants/rare_high_impact_variants.py \
  --input <input_file> --output <report_dir>

# Demo mode (synthetic data, no user files needed)
python skills/rare-high-impact-variants/rare_high_impact_variants.py --demo --output /tmp/rare_high_impact_variants_demo

# Via ClawBio runner
python clawbio.py run rare-high-impact-variants --input <file> --output <dir>
python clawbio.py run rare-high-impact-variants --demo

Demo

To verify the skill works:

python clawbio.py run rare-high-impact-variants --demo

Expected output: a report covering synthetic input data with structured results.

Algorithm / Methodology

1. **Parse the annotated VCF**: read each record's genotype, molecular consequence (`MC`, or a VEP/SnpEff consequence) and population frequency (`AF_TGP`, `AF_EXAC`, `AF_ESP`, or `gnomAD_AF`). 2. **Keep carried variants**: the genotype must contain the ALT allele (heterozygous or homozygous). 3. **Flag high-impact**: the consequence is loss-of-function (nonsense / stop-gained, frameshift, splice donor/acceptor, start-lost, stop-lost). 4. **Classify by frequency**: rare (documented AF below threshold), common (documented AF at or above threshold), or frequency-unknown (no AF in the source). Absence of a frequency is NOT counted as rare. 5. **Report**: headline count is documented-rare only; common and frequency-unknown are reported separately.

**Key thresholds / parameters**:

• `--max-af` rarity threshold, default `0.01` (1 per cent); ultra-rare band at AF < `0.001`.
• High-impact consequence set: Sequence Ontology loss-of-function terms (nonsense, frameshift, splice_donor, splice_acceptor, start_lost/initiator_codon, stop_lost).

Example Queries

• "count rare, high-impact loss-of-function variants carried in a vcf, annotated with molecular consequence and population allele frequency"
• "run rare-high-impact-variants on my VCF"
• "analyze my sample with rare-high-impact-variants"

Example Output

# Rare High-Impact Variants Report

**Input**: demo_input.txt
**