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/v4GRCh37— for v2
2. Querying Variants by Gene
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: $dataset) {
variant_id
pos
ref
alt
consequence
genome {
af
ac
an
ac_hom
populations {
id
ac
an
af
}
}
exome {
af
ac
an
ac_hom
}
lof
lof_flags
lof_filter
}
}
}
"""
variables = {
"gene_symbol": gene_symbol,
"dataset": dataset,
"reference_genome": reference_genome
}
response = requests.post(url, json={"query": query, "variables": variables})
return response.json()
# Example
result = query_gnomad_gene("BRCA1")
gene_data = result["data"]["gene"]
variants = gene_data["variants"]
# Filter to rare PTVs
rare_ptvs = [
v for v in variants
if v.get("lof") == "LC" or v.get("consequence") in ["stop_gained", "frameshift_variant"]
and v.get("genome", {}).get("af", 1) < 0.001
]
print(f"Found {len(rare_ptvs)} rare PTVs in {gene_data['gene_symbol']}")3. Querying a Specific Variant
import requests
def query_gnomad_variant(variant_id, dataset="gnomad_r4"):
"""Fetch details for a specific variant (e.g., '1-55516888-G-GA')."""
url = "https://gnomad.broadinstitute.org/api"
query = """
query VariantDetails($variantId: String!, $dataset: DatasetId!) {
variant(variantId: $variantId, dataset: $dataset) {
variant_id
chrom
pos
ref
alt
genome {
af
ac
an
ac_hom
populations {
id
ac
an
af
}
}
exome {
af
ac
an
ac_hom
populations {
id
ac
an
af
}
}
consequence
lof
rsids
in_silico_predictors {
id
value
flags
}
clinvar_variation_id
}
}
"""
response = requests.post(
url,
json={"query": query, "variables": {"variantId": variant_id, "dataset": dataset}}
)
return response.json()
# Example: query a specific variant
result = query_gnomad_variant("17-43094692-G-A") # BRCA1 missense
variant = result["data"]["variant"]
if variant:
genome_af = variant.get("genome", {}).get("af", "N/A")
exome_af = variant.get("exome", {}).get("af", "N/A")
print(f"Variant: {variant['variant_id']}")
print(f" Consequence: {variant['consequence']}")
print(f" Genome AF: {genome_af}")
print(f" Exome AF: {exome_af}")
print(f" LoF: {variant.get('lof')}")4. Gene Constraint Scores
gnomAD constraint scores assess how tolerant a gene is to variation relative to expectation:
import requests
def query_gnomad_constraint(gene_symbol, reference_genome="GRCh38"):
"""Fetch constraint scores for a gene."""
url = "https://gnomad.broadinstitute.org/api"
query = """
query GeneConstraint($gene_symbol: String!, $reference_genome: ReferenceGenomeId!) {
gene(gene_symbol: $gene_symbol, reference_genome: $reference_genome) {
gene_id
gene_symbol
gnomad_constraint {
exp_lof
exp_mis
exp_syn
obs_lof
obs_mis
obs_syn
oe_lof
oe_mis
oe_syn
oe_lof_lower
oe_lof_upper
lof_z
mis_z
syn_z
pLI
}
}
}
"""
response = requests.post(
url,
json={"query": query, "variables": {"gene_symbol": gene_symbol, "reference_genome": reference_genome}}
)
return response.json()
# Example
result = query_gnomad_constraint("KCNQ2")
gene = result["data"]["gene"]
constraint = gene["gnomad_constraint"]
print(f"Gene: {gene['gene_symbol']}")
print(f" pLI: {constraint['pLI']:.3f} (>0.9 = LoF intolerant)")
print(f" LOEUF: {constraint['oe_lof_upper']:.3f} (<0.35 = highly constrained)")
print(f" Obs/Exp LoF: {constraint['oe_lof']:.3f}")
print(f" Missense Z: {constraint['mis_z']:.3f}")Constraint score interpretation: | Score | Range | Meaning | |-------|-------|---------| | pLI | 0–1 | Probability of LoF intolerance; >0.9 = highly intolerant | | LOEUF | 0–∞ | LoF observed/expected upper bound; <0.35 = constrained | | oe_lof | 0–∞ | Observed/expected ratio for LoF variants | | mis_z | −∞ to ∞ | Missense constraint z-score; >3.09 = constrained | | syn_z | −∞ to ∞ | Synonymous z-score (control; should be near 0) |
5. Population Frequency Analysis
import requests
import pandas as pd
def get_population_frequencies(variant_id, dataset="gnomad_r4"):
"""Extract per-population allele frequencies for a variant."""
url = "https://gnomad.broadinstitute.org/api"
query = """
query PopFreqs($variantId: String!, $dataset: DatasetId!) {
variant(variantId: $variantId, dataset: $dataset) {
variant_id
genome {
populations {
id
ac
an
af
ac_hom
}
}
}
}
"""
response = requests.post(
url,
j