NM_000044.4:c.94G>A (p.Glu32Lys) in AR is a missense variant absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.1 Multiple computational predictors suggest no deleterious effect: BayesDel score is 0.079 (low/near-neutral) and SpliceAI predicts no splice impact (max delta 0.01), meeting BP4 at supporting strength.2 The variant has been reported in somatic cancers (COSMIC COSV65955976, n = 8) but has no ClinVar entry, no published germline disease association, and no functional characterization.3 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield insufficient evidence in either direction. This variant is classified as a Variant of Uncertain Significance (VUS).4
AR
Final classification
VUS
AR c.94G>A · p.Glu32Lys
AR
NM_000044.4:c.94G>A (p.Glu32Lys) in AR is a missense variant absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
AR c.94G>A
PM2 + BP4
→
VUS
2
bayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_000044.4 · variants mapped to exon structure
AR
NM_000044.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Applied at supporting strength per generic ACMG/AMP guidelines for absence from large population cohorts.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious effect: BayesDel score is 0.079 (low, near neutral range) and SpliceAI predicts no splicing impact (max delta score 0.01). REVEL is unavailable for this variant. The combined in silico evidence supports a benign interpretation.
BayesDel: 0.079 (low scoredoes not predict pathogenicity).SpliceAI: max delta 0.01 (no predicted splice-altering impact).
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant resulting in the same amino acid change (p.Glu32Lys) via a different nucleotide substitution has been identified in ClinVar or the published literature.
PS3
No well-established in vitro or in vivo functional studies demonstrating a deleterious effect have been identified for this variant.
PS4
No case-control studies have demonstrated a statistically significant increased prevalence of this variant in affected individuals compared to controls.
PM1
Variant lies in exon 1 of AR (NTD/AF1 transactivation domain, residue 32).
PP2
Insufficient data on gene-level missense constraint to determine whether AR has a low rate of benign missense variation.
PP3
Multiple in silico predictors do not support a deleterious effect: BayesDel score is 0.079 (low, near neutral), and SpliceAI predicts no splice impact (max delta score 0.01).
PP5
No reputable source (ClinVar, published literature) has reported this variant as pathogenic.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
This variant has not been observed in a healthy adult individual in a setting where full penetrance would be expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant.
BP1
AR-related disorders (androgen insensitivity syndrome) are caused by both missense and truncating variants; the disease mechanism is not one in which primarily truncating variants cause disease.
BP6
No reputable source (ClinVar, published literature) has classified this variant as benign.
N/A · 10
PVS1 · PS2 · PM5 · PM6 · PP1 · PP4 · BS4 · BP2 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.0786963.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65955976, n = 8 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links