About AR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AR c.515C>T, p.(Pro172Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/154879 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/10641 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: no assertion criteria provided.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 17 not met · 5 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 1
PM2 SupportingNM_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). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/154
- 879 alleles (0.00%)
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent.
Sources
Not met · 17 · evaluated, threshold not reached
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB reports no variant-specific reviewed functional evidence
- no PMIDs with functional characterization of p.Pro172Leu or a systematically assayed range covering this residue.
Still missing
- Absence of in vitro or in vivo functional studies for this variant or a systematically characterized range that includes codon 172.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission classified as VUS without case-level detail
- no published case series or case-control study identified.
Still missing
- No case-control or case-series data available for this variant.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Residue 172 is in the AR N-terminal domain
- cancerhotspots.org reports no significant hotspot at this residue
- no residue-specific functional domain defined at Pro172.
Still missing
- No defined critical functional subdomain specifically encompassing residue 172.
PM6 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. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV007126469 reports origin as 'maternal.'
Still missing
- No de novo observation for this variant.
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.277 (borderline damaging)
- SpliceAI max delta: 0.00 (no splice impact)
- REVEL: not found.
Still missing
- No corroborating in silico predictors
- BayesDel score is borderline.
Sources
bayesdelspliceai ↗
PP5 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). Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- no assertion criteria provided
- single submitter
- no expert panel review.
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/154
- 879 alleles (0.00%)
- gnomAD v4.1: absent.
Sources
BS1 NM_000044.4:c.515C>T is absent from population databases (gnomAD AF=0.00%), far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/154
- 879 alleles (0.00%)
- gnomAD v4.1: absent.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No healthy adult hemizygous male carriers identified.
Still missing
- No observation in healthy adult controls available.
BS3 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. Details ▾Hide ▴
Evidence considered
- No functional studies evaluating this variant for a benign effect.
Still missing
- No functional data available.
BS4 No segregation data are available to assess lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
- AIS is predominantly caused by missense variants in AR
- truncating variants are not the primary disease mechanism. GeneReviews confirms pathogenic variants are typically missense.
Sources
BP2 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. Details ▾Hide ▴
Evidence considered
- X-linked inheritance pattern
- BP2 observation in trans not applicable or no data.
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no splice impact)
- BayesDel: 0.277 (borderline damaging
- not benign)
- only one predictor suggests no impact.
Still missing
- No corroborating in silico predictors indicating a benign effect.
Sources
spliceai ↗bayesdel
BP5 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. Details ▾Hide ▴
Still missing
- No case with an alternate molecular cause identified.
BP6 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.' Details ▾Hide ▴
PS5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (Variation ID 4538436)
- review status: no assertion criteria provided.
Sources
Not assessed · 5 · no assessment recorded
PS1 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. Details ▾Hide ▴
Still missing
- No known pathogenic variant at codon 172 producing p.Pro172Leu via a different nucleotide substitution.
PS2 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. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV007126469 origin reported as 'maternal'.
Still missing
- No de novo observation with confirmed parentage available.
PP1 No co-segregation data are available for NM_000044.4:c.515C>T. No family studies with multiple affected members have been reported. Details ▾Hide ▴
Still missing
- No segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
- AR missense variants are known to cause AIS
- but no population constraint data for missense variation were available in the case packet.
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e) not available in case materials.
PP4 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. Details ▾Hide ▴
Still missing
- No proband phenotype or clinical history available in case materials.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Missense substitution not eligible for PVS1
- pvs1_variant_assessment confirms variant_bucket='other' with apply_generic_pvs1_framework=false.
Sources
PM3 N/APM3 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variants at AR codon 172 identified in ClinVar.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; NM_000044.4:c.515C>T is a single-nucleotide substitution, not an indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 172 (Pro→Leu).
Identifiers
- Gene
- AR
- Transcript
- NM_000044.4
- Coding (HGVS c.)
- NM_000044.4:c.515C>T
- Protein (HGVS p.)
- NP_000035.2:p.(Pro172Leu)
- GRCh38
- chrX:67545661 C>T
- GRCh37
- chrX:66765503 C>T
- ClinVar
- 4538436
Gene diagram
Every interpreted variant in AR, mapped onto the exon structure of NM_000044.4. Select a row to find it on the plot.
ARNM_000044.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in AR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
0 / 154,879 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v2.1
AF 0 · 0 / 154,879 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/154879 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/10641 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.277
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.277 (borderline damaging)
- SpliceAI max delta: 0.00 (no splice impact)
- REVEL: not found.
Still missing
- No corroborating in silico predictors
- BayesDel score is borderline.
Sources
bayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no splice impact)
- BayesDel: 0.277 (borderline damaging
- not benign)
- only one predictor suggests no impact.
Still missing
- No corroborating in silico predictors indicating a benign effect.
Sources
spliceai ↗bayesdel
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 172 (Pro→Leu).
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.276959.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301602 ↗Androgen Insensitivity Syndrome.Adam MP et al. · 1993GeneReviews clinical overview of Androgen Insensitivity Syndrome (AIS) describing AR-related clinical characteristics, diagnosis, management, and genetic counseling. The article discusses AR pathogenic variants broadly in the context of AIS diagnosis but does not list or discuss NM_000044.4:c.515C>T (p.Pro172Leu) specifically.Does not name this variant
Quoted passage
The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia [...] AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.
Abstract/Summary section of GeneReviews entry
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/4538436/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-66765503-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-67545661-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-67545661-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000044.4%3Ac.515C…
- OncoKB ↗www.oncokb.org/gene/AR/P172L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=AR+c.515C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/154879 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/10641 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4538436)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.276959.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.