rs9332969

Positions:

• chrX-67722899-G-A
• chrX-67722899-G-C
• chrX-67722899-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000044.6(AR):​c.2522G>A​(p.Arg841His) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R841G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.90

Genes affected

AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 18) in uniprot entity ANDR_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant X-67722899-G-A is Pathogenic according to our data. Variant chrX-67722899-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67722899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2522G>A	p.Arg841His	missense_variant	7/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.926G>A	p.Arg309His	missense_variant	8/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2522G>A	p.Arg841His	missense_variant	7/8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2019	Observed in several unrelated patients with androgen insensitivity syndrome in published literature (McPhaul et al., 1992; Beitel et al., 1994); Published functional studies demonstrate a damaging effect on GH gene promotion as well as ligand binding (Beitel et al., 1994); Not observed 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: 32985417, 3605226, 8040309, 28624954, 1430233, 28186600, 25241384, 16450583, 15835798, 27267075) -

Androgen resistance syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009829 / PMID: 1430233). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 1430233, 16450583, 25241384, 28624954, 32985417). Different missense changes at the same codon (p.Arg841Cys, p.Arg841Gly, p.Arg841Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009830 / PMID: 10502786, 1430233, 9856504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 30, 2007	- -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 04, 2023

Experimental studies have shown that this missense change affects AR function (PMID: 1430233, 8040309). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg941 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430233, 8040309, 8824883, 11788673, 15925895, 20011049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 9829). This variant is also known as p.R838H, p.R839H, and p.R840H. This missense change has been observed in individuals with androgen insensitivity syndome (PMID: 1430233, 8040309, 16450583, 25241384, 27267075, 28186600, 28624954). 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 841 of the AR protein (p.Arg841His). -

Partial androgen insensitivity syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.015	.;D;D
Sift4G	Uncertain	0.039	D;T;D
Vest4		0.83
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9332969; hg19: chrX-66942741; COSMIC: COSV65965338;