Query gnomAD for population allele frequencies to assess variant rarity. Use when filtering variants by population frequency for rare disease analysis or determining if a variant is common in the general population.
import requests
def query_gnomad(chrom, pos, ref, alt, dataset='gnomad_r4'):
'''Query gnomAD API for variant frequency
dataset options: gnomad_r4, gnomad_r3, gnomad_r2_1
'''
url = 'https://gnomad.broadinstitute.org/api'
query = '''
query ($variantId: String!, $dataset: DatasetId!) {
variant(variantId: $variantId, dataset: $dataset) {
exome {
ac
an
af
homozygote_count
}
genome {
ac
an
af
homozygote_count
}
}
}
'''
variant_id = f'{chrom}-{pos}-{ref}-{alt}'
variables = {'variantId': variant_id, 'dataset': dataset}
response = requests.post(url, json={'query': query, 'variables': variables})
return response.json()
def parse_gnomad_result(result):
'''Extract allele frequencies from gnomAD response'''
data = result.get('data', {}).get('variant', {})
if not data:
return None
exome = data.get('exome', {}) or {}
genome = data.get('genome', {}) or {}
return {
'exome_af': exome.get('af'),
'exome_ac': exome.get('ac'),
'exome_an': exome.get('an'),
'exome_hom': exome.get('homozygote_count'),
'genome_af': genome.get('af'),
'genome_ac': genome.get('ac'),
'genome_an': genome.get('an'),
'genome_hom': genome.get('homozygote_count')
}
import myvariant
mv = myvariant.MyVariantInfo()
def get_gnomad_via_myvariant(variant_hgvs):
'''Get gnomAD frequencies via myvariant.info'''
result = mv.getvariant(variant_hgvs, fields=['gnomad_exome', 'gnomad_genome'])
exome = result.get('gnomad_exome', {})
genome = result.get('gnomad_genome', {})
return {
'exome_af': exome.get('af', {}).get('af'),
'genome_af': genome.get('af', {}).get('af')
}
def get_population_frequencies(variant_hgvs):
'''Get gnomAD frequencies by ancestry population'''
mv = myvariant.MyVariantInfo()
result = mv.getvariant(variant_hgvs, fields=['gnomad_exome.af'])
af_data = result.get('gnomad_exome', {}).get('af', {})
populations = {
'af': af_data.get('af'), # Global
'af_afr': af_data.get('af_afr'), # African
'af_amr': af_data.get('af_amr'), # Admixed American
'af_asj': af_data.get('af_asj'), # Ashkenazi Jewish
'af_eas': af_data.get('af_eas'), # East Asian
'af_fin': af_data.get('af_fin'), # Finnish
'af_nfe': af_data.get('af_nfe'), # Non-Finnish European
'af_sas': af_data.get('af_sas'), # South Asian
}
return populations
Common frequency cutoffs for variant filtering:
| Threshold | Use Case |
|---|---|
| < 0.01 (1%) | Rare disease, ACMG PM2 |
| < 0.001 (0.1%) | Stringent rare disease |
| < 0.0001 (0.01%) | Ultra-rare |
| Absent | Novel variant |
def is_rare(gnomad_af, threshold=0.01):
'''Check if variant is rare based on gnomAD AF
threshold: Default 0.01 (1%) per ACMG PM2 supporting criterion
Use 0.001 for more stringent filtering
'''
if gnomad_af is None:
return True # Absent from gnomAD = rare
return gnomad_af < threshold
def filter_rare_variants(variants, threshold=0.01):
'''Filter list of variants to keep only rare ones'''
rare = []
for v in variants:
exome_af = v.get('gnomad_exome_af')
genome_af = v.get('gnomad_genome_af')
max_af = max(filter(None, [exome_af, genome_af]), default=None)
if is_rare(max_af, threshold):
rare.append(v)
return rare
For large-scale analysis, use local gnomAD VCF/Hail Table:
# Using Hail for gnomAD v4
import hail as hl
ht = hl.read_table('gs://gcp-public-data--gnomad/release/4.0/ht/exomes/gnomad.exomes.v4.0.sites.ht')
# Filter to rare variants
rare_ht = ht.filter(ht.freq[0].AF < 0.01)