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ARc.59G>AUncertain significance
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Variant interpretation report

AR c.59G>A, p.(Arg20Gln)

NM_000044.4:c.59G>A NP_000035.2:p.(Arg20Gln) View identifiers
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.

About AR

No gene-level summary was recorded for this case.

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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. In gnomAD v4.1, it is observed in 1 of 1,206,311 alleles (AF = 8.29e-07; 0.00008%), well below the PM2 threshold of 0.1%. It is absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the pathogenic range. These in silico findings are consistent with a benign impact.

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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 9 not met · 0 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (1/1,206,311 alleles, AF 8.29e-07), meeting PM2 at supporting level.

Multiple lines of in silico evidence predict no deleterious effect: SpliceAI max delta = 0.02 (no splicing impact) and BayesDel score = 0.226 (below pathogenic threshold), meeting BP4 at supporting benign level.

PVS1 is not applicable as this is a missense variant (p.Arg20Gln), not a predicted null variant.

No functional data, case-control studies, segregation data, or variant-specific publications were identified. PS3, PS4, and PM1 are not met.

ClinVar reports this variant as Uncertain significance (1 clinical laboratory, criteria provided). No expert panel classification is available.

The available evidence is insufficient to classify this variant as pathogenic or benign. One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, leaving the variant as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 rules.

Met · 2

PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v4.1, it is observed in 1 of 1,206,311 alleles (AF = 8.29e-07; 0.00008%), well below the PM2 threshold of 0.1%. It is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/1
  • 206
  • 311 alleles (AF 8.29e-07
  • 0 homozygotes)
  • gnomAD v2.1: absent
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence predict no deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the pathogenic range. These in silico findings are consistent with a benign impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no predicted splice alteration)
  • BayesDel: score = 0.225865 (below damaging threshold)
Still missing
  • REVEL score unavailable
  • HCI prior not applicable for AR.
Sources
spliceai ↗bayesdel

Not met · 9 · evaluated, threshold not reached

PS1 No same amino acid change (p.Arg20Gln) has been previously established as pathogenic independent of this variant. No data available to assess PS1. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic variant identified.
Still missing
  • No variant-specific literature or ClinVar entries report an established pathogenic same-amino-acid change.
PS3 No functional data exists for NM_000044.4:c.59G>A (p.Arg20Gln). OncoKB reports no variant-specific reviewed functional evidence. No publications in the literature packet contain functional characterization of this variant or a systematically characterized range that includes residue 20. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional data available.
Still missing
  • No functional studies (in vitro or in vivo) have assessed the impact of p.Arg20Gln on AR transcriptional activity
  • protein stability
  • or subcellular localization.
Sources
oncokb ↗
PS4 No case-control data or prevalence comparison between affected and unaffected individuals is available for this variant. Details ▾Hide ▴
Evidence considered
  • No case-control or cohort studies identified.
Still missing
  • No studies comparing variant frequency in AR-related disease cohorts vs. general population.
PM1 The variant (p.Arg20Gln) lies in the N-terminal transactivation domain of AR, but is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no variant-specific or domain-level functional characterization from the available publications supports PM1 application for this residue. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no significant hotspot at this residue. OncoKB: no curated domain-level evidence for this position.
Still missing
  • No publications establishing residue 20 as a critical functional residue within a well-characterized domain for germline AR disease.
Sources
oncokb ↗
PP2 AR does not meet the PP2 requirements. The gene has both missense and truncating pathogenic variants, and many benign missense variants are observed in AR. A low rate of benign missense variation cannot be established, and missense variants are not the predominant mechanism of disease to the exclusion of other variant types. Details ▾Hide ▴
Evidence considered
  • AR has diverse pathogenic mechanisms including missense
  • nonsense
  • frameshift
  • and CAG repeat expansion.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the damaging threshold. REVEL and HCI prior are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.02 (no predicted splicing impact)
  • BayesDel: score = 0.225865 (below pathogenic threshold)
Still missing
  • REVEL score unavailable for chrX:67545205.
Sources
spliceai ↗bayesdel
BA1 gnomAD v4.1 AF = 8.29e-07 (0.00008%) is far below the BA1 threshold of 1%. This variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF 8.29e-07 (1/1
  • 206
  • 311 alleles)
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 gnomAD v4.1 AF = 8.29e-07 (0.00008%) is far below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF 8.29e-07
  • well below the 0.3% BS1 cutoff.
Sources
gnomad_v4 ↗
BS3 No functional data demonstrating absence of deleterious effect exists for this variant. The literature reviewed contains no functional characterization of p.Arg20Gln or the surrounding region. Details ▾Hide ▴
Evidence considered
  • No well-established functional studies showing no damaging effect on AR protein function.
Still missing
  • No in vitro or in vivo functional studies assessing AR p.Arg20Gln.
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000044.4:c.59G>A is a missense variant (p.Arg20Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗
PS2 N/ANo de novo data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variants with established pathogenicity identified in ClinVar (0 candidates). Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates.
Sources
pm5_candidates
PM6 N/ANo de novo data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PP1 N/ANo segregation data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PP4 N/ANo phenotype specificity data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PP5 N/ANo segregation data available for this variant. PP5 is for variants with strong segregation evidence. Details ▾Hide ▴

No further detail was recorded.

BS2 N/ANo case-control or population segregation data available to assess observation in healthy individuals. Details ▾Hide ▴

No further detail was recorded.

BS4 N/ANo segregation data available for this variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AAR is not a gene for which primarily truncating variants are known to cause disease. Both missense and truncating pathogenic variants are well-documented in AR-related disorders (e.g., androgen insensitivity syndrome from missense variants, spinal and bulbar muscular atrophy from CAG repeat expansion). Details ▾Hide ▴
Evidence considered
  • AR has diverse pathogenic variant types
  • missense variants are a common mechanism of disease.
BP2 N/ANo data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ANo case-control data available. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ANo reputable source has reported this variant as benign; ClinVar classification is Uncertain significance by a single submitter (Ambry Genetics). Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (1 submitter
  • criteria provided).
Sources
clinvar ↗
BP7 N/AThis is a missense variant (c.59G>A, p.Arg20Gln). BP7 applies only to synonymous (silent) variants where splicing is predicted to be unaltered and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.
PS5 N/ANo segregation data available for this variant. PS5 is for variants with strong segregation evidence. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
AR
Transcript
NM_000044.4
Coding (HGVS c.)
NM_000044.4:c.59G>A
Protein (HGVS p.)
NP_000035.2:p.(Arg20Gln)
GRCh38
chrX:67545205 G>A
GRCh37
chrX:66765047 G>A
ClinVar
4129409

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…
gnomAD v4.1 1 / 1,206,311 alleles AF 8.29e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 8.3e-07 · 1 / 1,206,311 alleles · 0 hom
European (non-Finnish)1 / 894,288 1.1e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.28974e-07; MAF= 0.00008%, 1/1206311 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.11821e-06; MAF= 0.00011%, 1/894288 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +61 bp
0.000
SpliceAI acceptor gainat +26 bp
0.020
SpliceAI donor lossat +28 bp
0.000
SpliceAI donor gainat +215 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
0.226

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the pathogenic range. These in silico findings are consistent with a benign impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no predicted splice alteration)
  • BayesDel: score = 0.225865 (below damaging threshold)
Still missing
  • REVEL score unavailable
  • HCI prior not applicable for AR.
Sources
spliceai ↗bayesdel
PP3 Multiple lines of in silico evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the damaging threshold. REVEL and HCI prior are unavailable for this variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.02 (no predicted splicing impact)
  • BayesDel: score = 0.225865 (below pathogenic threshold)
Still missing
  • REVEL score unavailable for chrX:67545205.
Sources
spliceai ↗bayesdel
BP7 N/AThis is a missense variant (c.59G>A, p.Arg20Gln). BP7 applies only to synonymous (silent) variants where splicing is predicted to be unaltered and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.225865.

5 paper records 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

  • ACMG position statement on prenatal/preconception expanded carrier screening.
    ACMG position statement providing guidance on prenatal and preconception expanded carrier screening. Discusses criteria for disorder inclusion on screening panels, pretest counseling, and consent. Does not mention AR or the NM_000044.4:c.59G>A variant.
    Does not name this variant
    PMID 23619275 ↗
  • Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
    Edwards JG et al. · 2015
    Joint statement from ACMG, ACOG, NSGC, Perinatal Quality Foundation, and SMFM on expanded carrier screening in reproductive medicine. Provides points to consider for clinicians and laboratories offering expanded carrier screening panels. Does not mention AR or the NM_000044.4:c.59G>A variant.
    Does not name this variant
    PMID 25730230 ↗
  • Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
    Therrell BL et al. · 2013
    Recommendations regarding inclusion of newborn screening bloodspot collection device serial numbers on birth certificates. Discusses logistics of newborn screening programs. Does not mention AR or the NM_000044.4:c.59G>A variant.
    Does not name this variant
    PMID 23037933 ↗
  • Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
    Botkin JR et al. · 2014
    Guidelines from the Newborn Screening Translational Research Network (NBSTRN) on parental permission for pilot newborn screening research. Discusses ethical and consent frameworks. Does not mention AR or the NM_000044.4:c.59G>A variant.
    Does not name this variant
    PMID 24394680 ↗
  • ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
    ACOG Committee Opinion on newborn screening and the role of the obstetrician-gynecologist. Summarizes newborn screening programs and recommended clinical practices. Does not mention AR or the NM_000044.4:c.59G>A variant.
    Does not name this variant
    PMID 31022120 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,206,311 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 1 Uncertain significance 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.28974e-07; MAF= 0.00008%, 1/1206311 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.11821e-06; MAF= 0.00011%, 1/894288 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4129409)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.225865.

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.