rs754201976
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000044.6(AR):c.1847G>A(p.Arg616His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,401 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R616C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000044.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AR | NM_000044.6 | c.1847G>A | p.Arg616His | missense_variant | 3/8 | ENST00000374690.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AR | ENST00000374690.9 | c.1847G>A | p.Arg616His | missense_variant | 3/8 | 1 | NM_000044.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182900Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67520
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097401Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 362969
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 26, 2021 | Published functional studies demonstrate a damaging effect on androgen-responsive elements, decreasedDNA binding and transactivation ability (Mowszowicz et al., 1993; Beitel et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 8413310, 8162033, 8339746, 15531547, 25613104, 17054461, 11549642, 9627582, 29051026, 8723113, 24186138, 11181525, 9698822, 31012339, 32985417) - |
Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | This variant is also known as R614H, R615H, and R606H. This missense change has been observed in individuals with complete androgen insensitivity syndrome (CAIS) (PMID: 8162033, 8413310, 8723113, 9698822, 11549642, 15531547, 24186138, 25613104). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs754201976, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 616 of the AR protein (p.Arg616His). ClinVar contains an entry for this variant (Variation ID: 279684). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 8162033, 8413310, 11181525). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at