0%
ARc.2683delLikely pathogenic
Print report
Variant interpretation report

AR c.2683del, p.(Met895Ter)

NM_000044.4:c.2683del NP_000035.2:p.(Met895Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

NM_000044.4:c.2683delA is a frameshift deletion resulting in a premature termination codon at p.M895* in AR, where loss of function is a well-established mechanism for androgen insensitivity syndrome (OMIM:313700). The variant occurs in the last exon (exon 8/8) and is predicted to escape nonsense-mediated decay. However, the truncation removes the C-terminal 26 amino acids including the AF-2 coactivator interaction domain (helix 12) within the ligand-binding domain, which is critical to androgen receptor transcriptional activation. Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is applied at Strong strength for last-exon truncating variants affecting a critical functional domain.

PM2Moderate
PM2 · moderate

NM_000044.4:c.2683delA is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes). Absence from large population databases is consistent with a rare pathogenic variant in an X-linked disease gene.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 moderate; combination = 1 strong + 1 moderate, which maps to Likely Pathogenic.

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
0.190 maximum delta

Recorded SpliceAI maximum delta score: 0.190. 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.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV105928561, n = 1 times).

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.

29 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000044.4:c.2683delA (p.M895*) is a frameshift deletion in AR resulting in a premature termination codon in the last exon. AR loss of function is a well-established mechanism for androgen insensitivity syndrome. The variant escapes nonsense-mediated decay but truncates the critical AF-2 domain within the ligand-binding domain, meeting PVS1 at Strong strength per ClinGen SVI recommendations (PMC6185798).

NM_000044.4:c.2683delA is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at Moderate strength.

Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), 1 Strong criterion (PVS1_Strong) plus 1 Moderate criterion (PM2) supports a classification of Likely Pathogenic.

Met · 2

PVS1 StrongNM_000044.4:c.2683delA is a frameshift deletion resulting in a premature termination codon at p.M895* in AR, where loss of function is a well-established mechanism for androgen insensitivity syndrome (OMIM:313700). The variant occurs in the last exon (exon 8/8) and is predicted to escape nonsense-mediated decay. However, the truncation removes the C-terminal 26 amino acids including the AF-2 coactivator interaction domain (helix 12) within the ligand-binding domain, which is critical to androgen receptor transcriptional activation. Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is applied at Strong strength for last-exon truncating variants affecting a critical functional domain. Details ▾Hide ▴
Evidence considered
  • NM_000044.4:c.2683delA is a frameshift deletion creating a premature stop at p.M895*
  • AR loss of function is an established mechanism for androgen insensitivity syndrome (germline disease context confirmed)
  • Variant occurs in exon 8/8 (last exon)
  • NMD escape predicted
  • Truncation removes C-terminal 26 amino acids including AF-2/helix 12 of the ligand-binding domain
  • a critical functional region
  • ClinGen SVI PVS1 decision tree (PMC6185798): PVS1_Strong for last-exon null variants where the truncated region is critical to protein function
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_000044.4:c.2683delA is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes). Absence from large population databases is consistent with a rare pathogenic variant in an X-linked disease gene. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PP3 No computational evidence supports a deleterious effect for NM_000044.4:c.2683delA. SpliceAI predicts no significant splice impact (max delta score 0.19, below the 0.20 threshold). REVEL and BayesDel scores are not available for deletion variants. No other in silico tools support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.19 — no significant splice impact predicted
Sources
spliceai ↗
PP5 NM_000044.4:c.2683delA is absent from ClinVar. No reputable source has classified this variant as pathogenic, and no evidence has been made available for independent evaluation. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Sources
clinvar ↗
BA1 NM_000044.4:c.2683delA is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The variant does not meet the >1% population allele frequency threshold for BA1 under generic ACMG criteria. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_000044.4:c.2683delA is absent from population databases. The variant does not meet the >0.3% population allele frequency threshold for BS1 under generic ACMG criteria. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Insufficient computational evidence to suggest no impact on the gene or gene product. SpliceAI predicts no significant splice effect (max delta 0.19), but this represents a single line of evidence and the variant's primary pathogenic mechanism is protein truncation rather than aberrant splicing. Multiple independent lines of computational evidence supporting a benign effect are not available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.19 — no significant splice impact predicted
Sources
spliceai ↗
BP6 NM_000044.4:c.2683delA is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo data are available for NM_000044.4:c.2683delA. No publications or ClinVar submissions report de novo occurrence of this variant. Details ▾Hide ▴
Still missing
  • No de novo data available for this variant
PS3 No well-established functional studies are available for NM_000044.4:c.2683delA. No publications were identified that provide variant-specific functional evidence. Details ▾Hide ▴
Still missing
  • No functional studies found for this specific variant
PS4 NM_000044.4:c.2683delA is absent from ClinVar and no case-control or prevalence data are available. No publications report this variant in affected individuals. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No case-control or prevalence data available for this variant
Sources
clinvar ↗
PM1 The variant lies within the AR ligand-binding domain (aa 671-920), a critical functional domain. However, without a CSPEC/VCEP domain specification for PM1 in AR, and given that PVS1 already captures the functional significance of this truncating variant via domain-level considerations, PM1 is not independently assessed under the generic ACMG framework to avoid potential double-counting of domain-based evidence. Details ▾Hide ▴
Evidence considered
  • Variant at p.M895 lies within the AR ligand-binding domain (LBD
  • aa 671-920)
  • No CSPEC/VCEP domain specification available for independent PM1 assessment
Still missing
  • No VCEP/CSPEC domain criteria for PM1 in AR
PM6 No de novo data are available for NM_000044.4:c.2683delA. No publications or ClinVar submissions report de novo occurrence of this variant. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No co-segregation data are available for NM_000044.4:c.2683delA. No family studies were identified in the literature. Details ▾Hide ▴
Still missing
  • No co-segregation data available
PP4 No patient phenotype data are available for individuals harboring NM_000044.4:c.2683delA. No publications describe this variant in affected individuals. Details ▾Hide ▴
Still missing
  • No phenotype data available
BS2 No observations of NM_000044.4:c.2683delA in healthy adult controls are available. For an X-linked gene such as AR, observation in a healthy adult male would constitute strong benign evidence, but no such data exist for this variant. Details ▾Hide ▴
Still missing
  • No observations in healthy adult controls
BS3 No well-established functional studies demonstrating no deleterious effect are available for NM_000044.4:c.2683delA. No publications were identified that provide variant-specific functional evidence for benign impact. Details ▾Hide ▴
Still missing
  • No functional studies available
BS4 No co-segregation data are available to assess whether NM_000044.4:c.2683delA fails to segregate with disease. No family studies were identified. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No observations of NM_000044.4:c.2683delA in trans with a pathogenic variant (for an X-linked gene) or in cis with a pathogenic variant are available. No phase data exist for this variant. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 No observations of NM_000044.4:c.2683delA in an individual with an alternate molecular basis for disease. No relevant data are available. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a nucleotide substitution at the same position as a known pathogenic variant with the same predicted amino acid change. NM_000044.4:c.2683delA is a frameshift deletion, not a nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. AR is an X-linked gene; PM3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_000044.4:c.2683delA is a frameshift deletion resulting in a premature termination codon (p.M895*), not an in-frame deletion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator pathogenic missense variants were identified. PM5 requires a novel missense variant at an amino acid residue where a different pathogenic missense change has been previously established. Details ▾Hide ▴
Evidence considered
  • No comparator missense variants at residue M895 identified
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with low rates of benign missense variation where missense variants are a common disease mechanism. NM_000044.4:c.2683delA is a frameshift/nonsense variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_000044.4:c.2683delA is itself a truncating variant (frameshift/nonsense), not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_000044.4:c.2683delA is a frameshift deletion resulting in a premature termination codon, not an in-frame deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000044.4:c.2683delA is a frameshift/nonsense variant, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANo ClinVar submissions were found for NM_000044.4:c.2683delA. The variant is absent from the database, so no reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Sources
clinvar ↗

Identifiers

Gene
AR
Transcript
NM_000044.4
Coding (HGVS c.)
NM_000044.4:c.2683del
Protein (HGVS p.)
NP_000035.2:p.(Met895Ter)
GRCh38
chrX:67723758 GA>G
GRCh37
chrX:66943600 GA>G
COSMIC
COSV105928561

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 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

SpliceAI acceptor lossat -72 bp
0.010
SpliceAI acceptor gainat -401 bp
0.000
SpliceAI donor lossat -461 bp
0.010
SpliceAI donor gainat -19 bp
0.190
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.310

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 No computational evidence supports a deleterious effect for NM_000044.4:c.2683delA. SpliceAI predicts no significant splice impact (max delta score 0.19, below the 0.20 threshold). REVEL and BayesDel scores are not available for deletion variants. No other in silico tools support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.19 — no significant splice impact predicted
Sources
spliceai ↗
BP4 Insufficient computational evidence to suggest no impact on the gene or gene product. SpliceAI predicts no significant splice effect (max delta 0.19), but this represents a single line of evidence and the variant's primary pathogenic mechanism is protein truncation rather than aberrant splicing. Multiple independent lines of computational evidence supporting a benign effect are not available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.19 — no significant splice impact predicted
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000044.4:c.2683delA is a frameshift/nonsense variant, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19).

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 0.190 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

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 = 0.19).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105928561, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.