Variant classification summary

NM_000044.4:c.59G>A

AR · NP_000035.2:p.(Arg20Gln) · NM_000044.4

GRCh37: chrX:66765047 G>A · GRCh38: chrX:67545205 G>A

Gene: AR Transcript: NM_000044.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

AR

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Arg20Gln)

gnomAD AF

8.289736228882934e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (1/1,206,311 alleles, AF 8.29e-07), meeting PM2 at supporting level.

2

Multiple lines of in silico evidence predict no deleterious effect: SpliceAI max delta = 0.02 (no splicing impact) and BayesDel score = 0.226 (below pathogenic threshold), meeting BP4 at supporting benign level.

3

PVS1 is not applicable as this is a missense variant (p.Arg20Gln), not a predicted null variant.

4

No functional data, case-control studies, segregation data, or variant-specific publications were identified. PS3, PS4, and PM1 are not met.

5

ClinVar reports this variant as Uncertain significance (1 clinical laboratory, criteria provided). No expert panel classification is available.

6

The available evidence is insufficient to classify this variant as pathogenic or benign. One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, leaving the variant as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	NM_000044.4:c.59G>A is a missense variant (p.Arg20Gln). 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).	pvs1_generic_framework
PS1	Not met	No same amino acid change (p.Arg20Gln) has been previously established as pathogenic independent of this variant. No data available to assess PS1.
PS2	N/A	No de novo data available for this variant.
PS3	Not met	No functional data exists for NM_000044.4:c.59G>A (p.Arg20Gln). OncoKB reports no variant-specific reviewed functional evidence. No publications in the literature packet contain functional characterization of this variant or a systematically characterized range that includes residue 20.	oncokb
PS4	Not met	No case-control data or prevalence comparison between affected and unaffected individuals is available for this variant.
PS5	N/A	No segregation data available for this variant. PS5 is for variants with strong segregation evidence.
PM1	Not met	The variant (p.Arg20Gln) lies in the N-terminal transactivation domain of AR, but is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no variant-specific or domain-level functional characterization from the available publications supports PM1 application for this residue.	oncokb
PM2	Met	This variant is extremely rare in population databases. In gnomAD v4.1, it is observed in 1 of 1,206,311 alleles (AF = 8.29e-07; 0.00008%), well below the PM2 threshold of 0.1%. It is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with established pathogenicity identified in ClinVar (0 candidates).	pm5_candidates
PM6	N/A	No de novo data available for this variant.
PP1	N/A	No segregation data available for this variant.
PP2	Not met	AR does not meet the PP2 requirements. The gene has both missense and truncating pathogenic variants, and many benign missense variants are observed in AR. A low rate of benign missense variation cannot be established, and missense variants are not the predominant mechanism of disease to the exclusion of other variant types.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the damaging threshold. REVEL and HCI prior are unavailable for this variant.	spliceai bayesdel
PP4	N/A	No phenotype specificity data available for this variant.
PP5	N/A	No segregation data available for this variant. PP5 is for variants with strong segregation evidence.
BA1	Not met	gnomAD v4.1 AF = 8.29e-07 (0.00008%) is far below the BA1 threshold of 1%. This variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	gnomAD v4.1 AF = 8.29e-07 (0.00008%) is far below the BS1 threshold of 0.3%.	gnomad_v4
BS2	N/A	No case-control or population segregation data available to assess observation in healthy individuals.
BS3	Not met	No functional data demonstrating absence of deleterious effect exists for this variant. The literature reviewed contains no functional characterization of p.Arg20Gln or the surrounding region.
BS4	N/A	No segregation data available for this variant.
BP1	N/A	AR is not a gene for which primarily truncating variants are known to cause disease. Both missense and truncating pathogenic variants are well-documented in AR-related disorders (e.g., androgen insensitivity syndrome from missense variants, spinal and bulbar muscular atrophy from CAG repeat expansion).
BP2	N/A	No data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence predict no deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.02). BayesDel score = 0.226 is below the pathogenic range. These in silico findings are consistent with a benign impact.	spliceai bayesdel
BP5	N/A	No case-control data available.
BP6	N/A	No reputable source has reported this variant as benign; ClinVar classification is Uncertain significance by a single submitter (Ambry Genetics).	clinvar
BP7	N/A	This is a missense variant (c.59G>A, p.Arg20Gln). BP7 applies only to synonymous (silent) variants where splicing is predicted to be unaltered and the nucleotide is not highly conserved.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.