NM_000044.4:c.515C>T

AR · NP_000035.2:p.(Pro172Leu) · NM_000044.4

GRCh37: chrX:66765503 C>T · GRCh38: chrX:67545661 C>T

Gene: AR Transcript: NM_000044.4

Final call

VUS

PM2 supporting

Variant details

Gene

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Pro172Leu)

gnomAD AF

0.0 (v2.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000044.4:c.515C>T (p.Pro172Leu) is a missense variant in the androgen receptor (AR) gene, located on the X chromosome.

This variant is absent from large population databases including gnomAD v2.1 (0/154,879 alleles) and gnomAD v4.1, meeting PM2 at supporting strength.

No variant-specific functional, segregation, case-control, or de novo data were identified. ClinVar classifies this variant as Uncertain Significance (Variation ID 4538436) with a single submitter and no assertion criteria provided.

With only one supporting-level pathogenic criterion (PM2_supporting) and no benign criteria met, the overall classification is Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

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	NM_000044.4:c.515C>T is a missense variant (p.Pro172Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 is not applicable to missense substitutions under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No data available on a different nucleotide change at codon 172 producing the same amino acid change (Pro172Leu) that has been classified as pathogenic. PS1 cannot be evaluated without such a comparator.
PS2	Not assessed	No de novo reports for NM_000044.4:c.515C>T with confirmed maternity and paternity were identified. The single ClinVar submission (SCV007126469) reports maternal origin, consistent with inheritance rather than de novo occurrence.
PS3	Not met	No variant-specific functional evidence was identified for NM_000044.4:c.515C>T (p.Pro172Leu). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional data. No publications with experimental characterization of this variant or a systematically characterized range including position 172 were found.	oncokb
PS4	Not met	No case-control data or systematic case series demonstrating increased prevalence of NM_000044.4:c.515C>T in affected individuals compared to controls. The one ClinVar submission is a single observation without aggregated case-level data. PMID:20301602 is a GeneReviews overview of Androgen Insensitivity Syndrome and does not report variant-specific case counts.	clinvar
PS5	Not met	No reputable source has recently reported NM_000044.4:c.515C>T as pathogenic. The sole ClinVar classification is 'Uncertain significance' with review status 'no assertion criteria provided,' which does not meet the threshold for a reputable source assertion of pathogenicity.	clinvar
PM1	Not met	Residue Pro172 is located in the N-terminal transactivation domain (NTD) of AR (residues 1–555), which is a functionally important region. However, the NTD is a large domain and position 172 has not been specifically characterized as a critical functional subdomain residue. Cancerhotspots.org confirms this position is not in a statistically significant hotspot. Without residue-level hotspot data or a well-defined functional subdomain at position 172, PM1 is not met.
PM2	Met	NM_000044.4:c.515C>T is absent from large population databases: gnomAD v2.1 (0/154,879 alleles, AF=0.00%) and gnomAD v4.1 (absent). This meets the PM2 threshold for rare variants (allele frequency <0.1% in all populations).	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic comparator variants at codon 172 were identified in ClinVar. PM5 candidate harvesting found zero candidates; eligible_for_classic_pm5_search is false.	pm5_candidates
PM6	Not met	No de novo observation (assumed or confirmed) exists for this variant. The single ClinVar submission reports maternal origin, indicating inherited rather than de novo occurrence.	clinvar
PP1	Not assessed	No co-segregation data are available for NM_000044.4:c.515C>T. No family studies with multiple affected members have been reported.
PP2	Not assessed	AR is an X-linked gene where missense variants are a known mechanism of disease (Androgen Insensitivity Syndrome). However, no gene-level missense constraint metrics (e.g., gnomAD missense Z-score, o/e ratio) were available in the case materials to confirm a low rate of benign missense variation as required by PP2.
PP3	Not met	In silico evidence is insufficient to meet PP3: the sole available predictor (BayesDel score 0.277) is borderline and not corroborated by additional computational evidence. SpliceAI predicts no splicing impact (max delta 0.00), and REVEL data are unavailable. PP3 requires multiple lines of computational evidence supporting a deleterious effect.	bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data were provided in the case materials. PP4 requires the patient's phenotype to be highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classifies NM_000044.4:c.515C>T as 'Uncertain significance' (Variation ID 4538436) with review status 'no assertion criteria provided' and a single submitter using provider interpretation. This does not meet the PP5 threshold, which requires classification as pathogenic by a reputable source (e.g., expert panel with ≥3-star review status).	clinvar
BA1	Not met	NM_000044.4:c.515C>T is absent from gnomAD v2.1 (0/154,879 alleles) and gnomAD v4.1. The allele frequency is 0.00%, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000044.4:c.515C>T is absent from population databases (gnomAD AF=0.00%), far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_000044.4:c.515C>T in a healthy adult hemizygous male has been reported. Given AR is X-linked and AIS is expected to be fully penetrant in 46,XY individuals, observation in a healthy adult male would support BS2, but no such data exist.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect of NM_000044.4:c.515C>T (p.Pro172Leu) on AR protein function were identified.
BS4	Not met	No segregation data are available to assess lack of segregation with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. AR-related Androgen Insensitivity Syndrome is predominantly caused by missense variants, not truncating variants. Therefore BP1 does not apply.	PMID:20301602
BP2	Not met	AR is X-linked; Androgen Insensitivity Syndrome affects 46,XY individuals. Observation in trans with a pathogenic variant is not applicable to X-linked disorders in the same way as autosomal recessive disorders. No such data exist.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene product. While SpliceAI predicts no splicing impact (max delta 0.00), BayesDel score (0.277) is borderline damaging, not benign. Multiple lines of evidence suggesting a benign effect are not present.	spliceai bayesdel
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring NM_000044.4:c.515C>T. No such data exist in the case materials.
BP6	Not met	No reputable source classifies NM_000044.4:c.515C>T as benign. ClinVar reports 'Uncertain significance' (Variation ID 4538436) with review status 'no assertion criteria provided.'	clinvar
BP7	N/A	NM_000044.4:c.515C>T is a missense variant (p.Pro172Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; NM_000044.4:c.515C>T is a single-nucleotide substitution, not an indel.
PM3	N/A	PM3 applies to autosomal/X-linked recessive disorders where a variant is observed in trans with a pathogenic variant. AR-related AIS affects 46,XY individuals and follows X-linked inheritance; PM3 in trans observation is not structurally applicable.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. NM_000044.4:c.515C>T is a missense substitution, not a length-altering variant.

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