NM_000044.6:c.2668G>A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000044.6(AR):c.2668G>A(p.Val890Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000044.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182688Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67360
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
Androgen resistance syndrome Pathogenic:3
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 8126121). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279690 / PMID: 10425033). A different missense change at the same codon (p.Val890Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430163, VCV001338633 / PMID: 20150575). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, however the androgen insensitivity (AIS) phenotype is known to only be caused by variants resulting in a loss-of-function (OMIM, PMID: 22334387). (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Minor amino acid change, very high conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternate change to leucine at the same residue has previously been reported as pathogenic in at least two patients with AIS (ClinVar, HGMD, PMID: 20150575). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with both complete and partial AIS (ClinVar, HGMD, PMID: 10425033, PMID: 24737579, PMID: 27051040). (P) 0903 - Low evidence for segregation with disease. The variant has previously been shown to segregate with AIS in at least one family (PMID: 29785970). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies of the variant in transfected cells demonstrated reduced androgen binding capacity (PMID: 8126121). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 890 of the AR protein (p.Val890Met). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individuals with complete androgen insensitivity syndrome (PMID: 10690872, 14974091, 15925895, 20150575, 24737579). This variant is also known as p.Val889Met and p.Val888Met. ClinVar contains an entry for this variant (Variation ID: 279690). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. Experimental studies have shown that this missense change affects AR function (PMID: 8126121). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Published functional studies found this variant is associated with significant impairment of androgen binding capacity (de Bellis et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Missense variants in this gene are often considered pathogenic (HGMD); Also known as p.(V889M); This variant is associated with the following publications: (PMID: 29785970, 26522496, 14974091, 27802905, 10690872, 10425033, 20150575, 15925895, 27051040, 27022412, 33516834, 24737579, 8126121) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at