Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
AR
Final classification
Likely Pathogenic
PVS1PM2
AR
c.2683del
p.Met895Ter
This variant

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).

Transcript
NM_000044.4
HGVS · transcript:coding
NM_000044.4:c.2683del
GRCh38
chrX:67723758 GA>G
GRCh37
chrX:66943600 GA>G
Basis 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. ▾
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.
Classification rationale
PVS1PM2 Likely Pathogenic
AR c.2683del

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).1 NM_000044.4:c.2683delA is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at Moderate strength.2 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.3

PVS1 + PM2 → Likely Pathogenic
1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 generic_acmg_combination_rules
Gene diagram · NM_000044.4 · variants mapped to exon structure
AR NM_000044.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 strong Pathogenic
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.
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)
pvs1_generic_framework ↗
✓
PM2 moderate Pathogenic
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.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (HostSeq genomes)
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 6 not met · 12 not assessed
Pathogenic
PS2 No de novo data are available for NM_000044.4:c.2683delA.
PS3 No well-established functional studies are available for NM_000044.4:c.2683delA.
PS4 NM_000044.4:c.2683delA is absent from ClinVar and no case-control or prevalence data are available.
PM1 The variant lies within the AR ligand-binding domain (aa 671-920), a critical functional domain.
PM6 No de novo data are available for NM_000044.4:c.2683delA.
PP1 No co-segregation data are available for NM_000044.4:c.2683delA.
PP3 No computational evidence supports a deleterious effect for NM_000044.4:c.2683delA.
PP4 No patient phenotype data are available for individuals harboring NM_000044.4:c.2683delA.
PP5 NM_000044.4:c.2683delA is absent from ClinVar.
Benign
BA1 NM_000044.4:c.2683delA is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1 NM_000044.4:c.2683delA is absent from population databases.
BS2 No observations of NM_000044.4:c.2683delA in healthy adult controls are available.
BS3 No well-established functional studies demonstrating no deleterious effect are available for NM_000044.4:c.2683delA.
BS4 No co-segregation data are available to assess whether NM_000044.4:c.2683delA fails to segregate with disease.
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.
BP4 Insufficient computational evidence to suggest no impact on the gene or gene product.
BP5 No observations of NM_000044.4:c.2683delA in an individual with an alternate molecular basis for disease.
BP6 NM_000044.4:c.2683delA is absent from ClinVar.
N/A · 8 PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105928561, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots