Variant classification summary

NM_000044.4:c.2683delA

AR · NP_000035.2:p.(Met895Ter) · NM_000044.4

GRCh37: chrX:66943600 GA>G · GRCh38: chrX:67723758 GA>G

Gene: AR Transcript: NM_000044.4

Final call

Likely Pathogenic

PVS1 strong PM2 moderate

Variant details

Gene

AR

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Met895Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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

3

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not assessed	No de novo data are available for NM_000044.4:c.2683delA. No publications or ClinVar submissions report de novo occurrence of this variant.
PS3	Not assessed	No well-established functional studies are available for NM_000044.4:c.2683delA. No publications were identified that provide variant-specific functional evidence.
PS4	Not assessed	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.	clinvar
PS5	N/A	No 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.	clinvar
PM1	Not assessed	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	No de novo data are available for NM_000044.4:c.2683delA. No publications or ClinVar submissions report de novo occurrence of this variant.
PP1	Not assessed	No co-segregation data are available for NM_000044.4:c.2683delA. No family studies were identified in the literature.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not assessed	No patient phenotype data are available for individuals harboring NM_000044.4:c.2683delA. No publications describe this variant in affected individuals.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not assessed	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.
BS4	Not assessed	No co-segregation data are available to assess whether NM_000044.4:c.2683delA fails to segregate with disease. No family studies were identified.
BP1	N/A	BP1 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.
BP2	Not assessed	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.
BP3	N/A	BP3 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.
BP4	Not met	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.	spliceai
BP5	Not assessed	No observations of NM_000044.4:c.2683delA in an individual with an alternate molecular basis for disease. No relevant data are available.
BP6	Not met	NM_000044.4:c.2683delA is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_000044.4:c.2683delA is a frameshift/nonsense variant, not a synonymous variant.

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