rs9332969

Variant names:

• chrX-67722899-G-A
• rs9332969
• NM_000044.6:c.2522G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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. R841C) has been classified as 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
• Publications: 22 publications found

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]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chrX-67722898-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.
• 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 VariationId is 9829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 10, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 21, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Androgen resistance syndrome Pathogenic:2

Nov 30, 2007

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. 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 /3billion dataset). 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. -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Jul 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects AR function (PMID: 1430233, 8040309). 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). This variant is not present in population databases (gnomAD no frequency). 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 also known as p.R838H, p.R839H, and p.R840H. ClinVar contains an entry for this variant (Variation ID: 9829). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Partial androgen insensitivity syndrome Pathogenic:1

Aug 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		5.9
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
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs9332969; hg19: chrX-66942741;