gnomad-database

Files (3)

• SKILL.md
• graphql_queries.md · references/
• variant_interpretation.md · references/

SKILL.md (first lines)

# gnomAD Database

## Overview

The Genome Aggregation Database (gnomAD) is the largest publicly available collection of human genetic variation, aggregated from large-scale sequencing projects. gnomAD v4 contains exome sequences from 730,947 individuals and genome sequences from 76,215 individuals across diverse ancestries. It provides population allele frequencies, variant consequence annotations, and gene-level constraint metrics that are essential for interpreting the clinical significance of genetic variants.

**Key resources:**
- gnomAD browser: https://gnomad.broadinstitute.org/
- GraphQL API: https://gnomad.broadinstitute.org/api
- Data downloads: https://gnomad.broadinstitute.org/downloads
- Documentation: https://gnomad.broadinstitute.org/help

## When to Use This Skill

Use gnomAD when:

- **Variant frequency lookup**: Checking if a variant is rare, common, or absent in the general population
- **Pathogenicity assessment**: Rare variants (MAF < 1%) are candidates for disease causation; gnomAD helps filter benign common variants
- **Loss-of-function intolerance**: Using pLI and LOEUF scores to assess whether a gene tolerates protein-truncating variants
- **Population-stratified frequencies**: Comparing allele frequencies across ancestries (African/African American, Admixed American, Ashkenazi Jewish, East Asian, Finnish, Middle Eastern, Non-Finnish European, South Asian)
- **ClinVar/ACMG variant classification**: gnomAD frequency data feeds into BA1/BS1 evidence codes for variant classification
- **Constraint analysis**: Identifying genes depleted of missense or loss-of-function variation (z-scores, pLI, LOEUF)

## Core Capabilities

### 1. gnomAD GraphQL API

gnomAD uses a GraphQL API accessible at `https://gnomad.broadinstitute.org/api`. Most queries fetch variants by gene or specific genomic position.

**Datasets available:**
- `gnomad_r4` — gnomAD v4 exomes (recommended default, GRCh38)
- `gnomad_r4_genomes` — gnomAD v4 genomes (GRCh38)
- `gnomad_r3` — gnomAD v3 genomes (GRCh38)
- `gnomad_r2_1` — gnomAD v2 exomes (GRCh37)

**Reference genomes:**
- `GRCh38` — default for v3/v4
- `GRCh37` — for v2

### 2. Querying Variants by Gene

```python
import requests

def query_gnomad_gene(gene_symbol, dataset="gnomad_r4", reference_genome="GRCh38"):
    """Fetch variants in a gene from gnomAD."""
    url = "https://gnomad.broadinstitute.org/api"

    query = """
    query GeneVariants($gene_symbol: String!, $dataset: DatasetId!, $reference_genome: ReferenceGenomeId!) {
      gene(gene_symbol: $gene_symbol, reference_genome: $reference_genome) {
        gene_id
        gene_symbol
        variants(dataset: $dataset) {
          variant_id
          pos
          ref
          alt
          consequence
          genome {
            af
            ac
            an
            ac_hom
            populations {
              id
              ac
              an
              af
            }
          }
          exome {
            af
            ac
            an
            ac_hom
          }
          lof
          lof_flags
          lof_filter
        }
      }
    }
    """

    variables = {
        "gene_symbol": gene_symbol,
        "dataset": dataset,
        "reference_genome": reference_genome
    }

    response = requests.post(url, json={"query": query, "variables": variables})
    return response.json()

# Example
result = query_gnomad_gene("BRCA1")
gene_data = result["data"]["gene"]
variants = gene_data["variants"]

# Filter to rare PTVs
rare_ptvs = [
    v for v in variants
    if v.get("lof") == "LC" or v.get("consequence") in ["stop_gained", "frameshift_variant"]
    and v.get("genome", {}).get("af", 1) < 0.001
]
print(f"Found {len(rare_ptvs)} rare PTVs in {gene_data['gene_symbol']}")
```

### 3. Querying a Specific Variant

```python
import requests

def query_gnomad_variant(variant_id, dataset="gnomad_r4"):
    """Fetch details for a specific variant (e.g., '1-55516888-G-GA')."""
    url = "https://gnomad.broadinstitute.org/api"

    query = """
    query VariantDetails($variantId: String!, $dataset: DatasetId!) {

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