About AR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AR c.94G>A, p.(Glu32Lys)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Applied at supporting strength per generic ACMG/AMP guidelines for absence from large population cohorts.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious effect: BayesDel score is 0.079 (low, near neutral range) and SpliceAI predicts no splicing impact (max delta score 0.01). REVEL is unavailable for this variant. The combined in silico evidence supports a benign interpretation.
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; 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
8 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV65955976, n = 8 times).
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.
26 criteria with recorded statuses: 2 met · 12 not met · 1 not assessed · 11 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.94G>A (p.Glu32Lys) in AR is a missense variant absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.
Multiple computational predictors suggest no deleterious effect: BayesDel score is 0.079 (low/near-neutral) and SpliceAI predicts no splice impact (max delta 0.01), meeting BP4 at supporting strength.
The variant has been reported in somatic cancers (COSMIC COSV65955976, n = 8) but has no ClinVar entry, no published germline disease association, and no functional characterization.
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield insufficient evidence in either direction. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Applied at supporting strength per generic ACMG/AMP guidelines for absence from large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes/genomes).
- Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect: BayesDel score is 0.079 (low, near neutral range) and SpliceAI predicts no splicing impact (max delta score 0.01). REVEL is unavailable for this variant. The combined in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.079 (low score
- does not predict pathogenicity).
- SpliceAI: max delta 0.01 (no predicted splice-altering impact).
Still missing
- REVEL score unavailable.
Sources
bayesdelspliceai ↗
Not met · 12 · evaluated, threshold not reached
PS1 No known pathogenic variant resulting in the same amino acid change (p.Glu32Lys) via a different nucleotide substitution has been identified in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
- ClinVar search for AR residue 32 returned no pathogenic missense variants with a different nucleotide change.
Sources
PS3 No well-established in vitro or in vivo functional studies demonstrating a deleterious effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific curated functional studies found.
Still missing
- No functional studies available for p.Glu32Lys in AR.
Sources
PS4 No case-control studies have demonstrated a statistically significant increased prevalence of this variant in affected individuals compared to controls. The variant is absent from ClinVar and has no reported clinical observations. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- absent from gnomAD
- no published case-control data.
Still missing
- No affected-vs-control prevalence data available.
Sources
PM1 Variant lies in exon 1 of AR (NTD/AF1 transactivation domain, residue 32). This position is not within a statistically significant mutational hotspot per cancerhotspots.org, and no ClinVar hotspot cluster has been established for this residue. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots (cancerhotspots.org): residue 32 is not a statistically significant hotspot
- no domain-level VCEP hotspot criteria available.
PP3 Multiple in silico predictors do not support a deleterious effect: BayesDel score is 0.079 (low, near neutral), and SpliceAI predicts no splice impact (max delta score 0.01). REVEL score is unavailable. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.079 (low score
- does not support pathogenicity).
- SpliceAI: max delta 0.01 (no predicted splice impact).
Still missing
- REVEL score unavailable for this variant on chrX.
Sources
bayesdelspliceai ↗
PP5 No reputable source (ClinVar, published literature) has reported this variant as pathogenic. The variant is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no expert panel or clinical laboratory has classified this variant as pathogenic.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Its allele frequency is 0%, which does not exceed the BA1 threshold (>1%). Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in all gnomAD datasets
- does not meet BA1 threshold (>1%).
Sources
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Its allele frequency is 0%, which does not exceed the BS1 threshold (>0.3%). Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in all gnomAD datasets
- does not meet BS1 threshold (>0.3%).
Sources
BS2 This variant has not been observed in a healthy adult individual in a setting where full penetrance would be expected at an early age. The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
- No observation in healthy controls with expected early-onset full penetrance.
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies (benign or pathogenic) available for p.Glu32Lys in AR.
Still missing
- No functional characterization of p.Glu32Lys has been performed.
BP1 AR-related disorders (androgen insensitivity syndrome) are caused by both missense and truncating variants; the disease mechanism is not one in which primarily truncating variants cause disease. BP1 does not apply to genes where missense variants are a well-established pathogenic mechanism. Details ▾Hide ▴
Evidence considered
- AR loss-of-function mechanism includes both missense and truncating variants in androgen insensitivity syndrome per germline disease context.
Sources
pvs1_gene_context
BP6 No reputable source (ClinVar, published literature) has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any submitter.
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient data on gene-level missense constraint to determine whether AR has a low rate of benign missense variation. No gnomAD missense Z-score or comparable constraint metric is available in the evidence packet for this X-linked gene. Details ▾Hide ▴
Evidence considered
- No missense constraint metrics (Z-score
- o/e) available for AR.
Still missing
- Requires gene-level missense constraint data (e.g.
- gnomAD missense Z-score) to assess PP2.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000044.4:c.94G>A is a missense variant (p.Glu32Lys); 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 substitution
- not a predicted null variant
- apply_generic_pvs1_framework is false.
Sources
PS2 N/ANo de novo testing with confirmed parentage has been performed or reported for this variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo known pathogenic missense variant at the same amino acid residue (Glu32) has been identified in ClinVar to serve as a PM5 comparator. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue pathogenic comparators at residue 32.
Sources
pm5_candidates
PM6 N/ANo de novo observation has been reported for this variant, with or without confirmed parentage. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo family segregation data are available for cosegregation analysis. Details ▾Hide ▴
No further detail was recorded.
PP4 N/ANo patient phenotype or clinical data are available to assess whether the proband's features are specific for an AR-related disorder. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo family segregation data are available to assess nonsegregation with disease. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo phase data are available; the variant has not been observed in trans with a pathogenic variant or in cis with a known pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo clinical data are available to determine whether an alternate molecular basis for disease has been identified in a proband carrying this variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.94G>A, p.Glu32Lys), not a synonymous variant. BP7 applies only to silent variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 restricted to synonymous variants.
PS5 N/APS5 is not a recognized ACMG/AMP 2015 criterion code. No equivalent criterion applies. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- AR
- Transcript
- NM_000044.4
- Coding (HGVS c.)
- NM_000044.4:c.94G>A
- Protein (HGVS p.)
- NP_000035.2:p.(Glu32Lys)
- GRCh38
- chrX:67545240 G>A
- GRCh37
- chrX:66765082 G>A
- COSMIC
- COSV65955976
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
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.079
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect: BayesDel score is 0.079 (low, near neutral range) and SpliceAI predicts no splicing impact (max delta score 0.01). REVEL is unavailable for this variant. The combined in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.079 (low score
- does not predict pathogenicity).
- SpliceAI: max delta 0.01 (no predicted splice-altering impact).
Still missing
- REVEL score unavailable.
Sources
bayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect: BayesDel score is 0.079 (low, near neutral), and SpliceAI predicts no splice impact (max delta score 0.01). REVEL score is unavailable. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.079 (low score
- does not support pathogenicity).
- SpliceAI: max delta 0.01 (no predicted splice impact).
Still missing
- REVEL score unavailable for this variant on chrX.
Sources
bayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.94G>A, p.Glu32Lys), not a synonymous variant. BP7 applies only to silent variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.0786963.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.010
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/?term=NM_000044.4%3Ac.94G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-66765082-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-67545240-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-67545240-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000044.4%3Ac.94G%…
- OncoKB ↗www.oncokb.org/gene/AR/E32K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=141149886
- 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
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.0786963.
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 previously been reported in somatic cancers (COSMIC; COSV65955976, n = 8 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.