rs9332971
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000044.6(AR):c.2567G>A(p.Arg856His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R856C) has been classified as Pathogenic.
Frequency
Consequence
NM_000044.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AR | NM_000044.6 | c.2567G>A | p.Arg856His | missense_variant | 7/8 | ENST00000374690.9 | |
AR | NM_001011645.3 | c.971G>A | p.Arg324His | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AR | ENST00000374690.9 | c.2567G>A | p.Arg856His | missense_variant | 7/8 | 1 | NM_000044.6 | P1 | |
AR | ENST00000396044.8 | c.2174-742G>A | intron_variant | 1 | |||||
AR | ENST00000396043.4 | c.*915G>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/9 | 1 | ||||
AR | ENST00000612452.5 | c.2567G>A | p.Arg856His | missense_variant, NMD_transcript_variant | 7/9 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Androgen resistance syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 20, 2023 | ACMG:PM1 PM2 PP3 PP4 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Partial androgen insensitivity syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1993 | - - |
Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg856 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581399, 24321103). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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"). ClinVar contains an entry for this variant (Variation ID: 9823). This variant is also known as R853H and 2926G>A (R855H). This missense change has been observed in individuals with partial androgen insensitivity syndrome (PMID: 1430233, 8097257, 24737579). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 856 of the AR protein (p.Arg856His). - |
Male infertility Pathogenic:1
Pathogenic, criteria provided, single submitter | in vitro;research | Institute of Reproductive Genetics, University of Münster | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at