Analysis in progress

Initialising…

complete

This report is still being assembled — sections appear as each stage finishes. It isn't final yet.

Final classification

Likely Pathogenic

AR c.2683del · p.Met895Ter

Gene

Transcript

NM_000044.4

HGVS · transcript:coding

NM_000044.4:c.2683del

Consequence

N/A

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

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