NM_000044.4:c.455C>T

AR · NP_000035.2:p.(Pro152Leu) · NM_000044.4

GRCh37: chrX:66765443 C>T · GRCh38: chrX:67545601 C>T

Gene: AR Transcript: NM_000044.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Pro152Leu)

gnomAD AF

8.418273715118883e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

Insufficient evidence to classify as pathogenic or benign. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 framework.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (c.455C>T, p.Pro152Leu) does not fall into PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant-level generic PVS1 assessment confirms apply_generic_pvs1_framework = false.	pvs1_variant_assessment
PS1	Not assessed	No prior pathogenic variant at this nucleotide position identified. Absent from ClinVar; no literature reports of a pathogenic variant at NM_000044.4:c.455.	clinvar
PS2	Not assessed	No de novo occurrence data available. No family studies or case reports identified for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publications with functional data for NM_000044.4:c.455C>T.	oncokb
PS4	Not assessed	No case-control or prevalence data comparing affected individuals to general population controls available.
PS5	Not assessed	No alternative pathogenic variant at the same amino acid residue (Pro152) identified. PM5 candidate harvesting could not identify same-residue comparator variants; no alternative missense changes at codon 152 found in ClinVar.	pm5_candidates
PM1	Not met	Variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org). Pro152 resides in the N-terminal transactivation domain of AR, which is not an established critical functional domain with high pathogenic missense constraint.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not assessed	No pathogenic missense variant at the same amino acid residue (Pro152) identified as a comparator. PM5 candidate harvesting could not find same-residue ClinVar entries; no alternative pathogenic missense at this codon.	pm5_candidates
PM6	Not assessed	No de novo occurrence data available. No family studies or case reports with confirmed maternity/paternity identified for this variant.
PP1	Not assessed	No cosegregation data available. No family studies with multiple affected individuals identified for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants. AR has known pathogenic missense variants predominantly in the ligand-binding domain, but Pro152 resides in the N-terminal transactivation domain where missense constraint is not established. No HCI prior or gene-specific missense constraint metric available to support PP2.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. BayesDel score = -0.012 (negative, falls in benign range). SpliceAI max delta = 0.00 (no predicted splicing alteration). REVEL score not available. Without multiple concordant deleterious in silico predictions, PP3 is not met.	bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical information provided for this case. Without phenotype data, cannot assess specificity of presentation for AR-related disease.
PP5	Not met	Not reported as pathogenic by a reputable source. This variant is absent from ClinVar entirely; no expert panel or clinical laboratory has submitted a pathogenic classification.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not assessed	No data on observation in healthy adults with full penetrance expected at an early age. AR-related disorders (e.g., androgen insensitivity syndrome) have variable expressivity and the X-linked inheritance pattern complicates BS2 application without individual-level clinical data.
BS3	Not assessed	No well-established functional studies showing no damaging effect for this variant. No variant-specific functional data identified in the literature or curated databases.
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease in affected families.
BP1	Not met	BP1 applies to missense variants in genes where truncating variants are the primary/only disease mechanism. AR missense variants are well-established causes of androgen insensitivity syndrome and other AR-related disorders; therefore, a missense change does not qualify for BP1.
BP2	Not assessed	No data on observation in trans with a pathogenic variant. For X-linked AR, hemizygous males cannot have a trans configuration; in females, X-inactivation patterns and clinical data would be required.
BP3	N/A	Variant is a single nucleotide substitution, not an in-frame deletion/insertion in a repetitive region.
BP4	Met	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 spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in an individual harboring this variant.
BP6	Not assessed	Not reported as benign by a reputable source. This variant is absent from ClinVar; no benign classification from any submitter.	clinvar
BP7	N/A	Variant is a missense change (c.455C>T, p.Pro152Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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