NM_000044.4:c.455C>T (p.Pro152Leu) in AR is a missense variant in the N-terminal transactivation domain. This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles), fulfilling PM2 at supporting strength.1 In silico predictions are concordantly benign: BayesDel scores -0.012 (benign range) and SpliceAI predicts no splicing alteration (max delta = 0.00), supporting BP4 at supporting level.2 One supporting pathogenic criterion (PM2_supporting) and one supporting benign criterion (BP4_supporting) offset each other. The variant is absent from ClinVar, has no functional data, and no literature reports.3 Insufficient evidence to classify as pathogenic or benign. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 framework.4
AR
Final classification
VUS
AR c.455C>T · p.Pro152Leu
AR
NM_000044.4:c.455C>T (p.Pro152Leu) in AR is a missense variant in the N-terminal transactivation domain.
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.455C>T
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 · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
Extremely low frequency in population databases. Absent from gnomAD v2.1. Present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles; 0 homozygotes), well below the 0.1% PM2 threshold. The single observed allele is in a hemizygous male of European (non-Finnish) ancestry. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: absent.gnomAD v4.1: AF = 8.42 × 10⁻⁷ (1/1187
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score = -0.0120934 (negative value, consistent with benign prediction). SpliceAI max delta score = 0.00 (no predicted splicing alteration). REVEL was unavailable; however, the concordance of available in silico tools supports BP4 at supporting level.
BayesDel: -0.012 (benign range).SpliceAI max delta: 0.00 (no splice alteration).
Assessed · not applied
Pathogenic
PS1
No prior pathogenic variant at this nucleotide position identified.
PS2
No de novo occurrence data available.
PS3
No well-established in vitro or in vivo functional studies identified for this variant.
PS4
No case-control or prevalence data comparing affected individuals to general population controls available.
PM1
Variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org).
PM5
No pathogenic missense variant at the same amino acid residue (Pro152) identified as a comparator.
PM6
No de novo occurrence data available.
PP1
No cosegregation data available.
PP2
PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or clinical information provided for this case.
PP5
Not reported as pathogenic by a reputable source.
Benign
BA1
Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BA1 threshold of >1%.
BS1
Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BS1 threshold of >0.3%.
BS2
No data on observation in healthy adults with full penetrance expected at an early age.
BS3
No well-established functional studies showing no damaging effect for this variant.
BS4
No segregation data available to assess lack of cosegregation with disease in affected families.
BP1
BP1 applies to missense variants in genes where truncating variants are the primary/only disease mechanism.
BP2
No data on observation in trans with a pathogenic variant.
BP5
No data on an alternate molecular basis for disease in an individual harboring this variant.
BP6
Not reported as benign by a reputable source.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.41827e-07; MAF= 0.00008%, 1/1187892 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.13202e-06; MAF= 0.00011%, 1/883379 alleles, homozygotes = 0).
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
8.4e-05%
· 1 / 1,187,892
0 hom
0 hom
European (non-Finnish) 1 / 883,379 |
0.00011% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 = 0.00). BayesDel score = -0.0120934.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links