rs9332971

Variant names:

• chrX-67722944-G-A
• rs9332971
• NM_000044.6:c.2567G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-67722944-G-A
• chrX-67722944-G-C
• chrX-67722944-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 14 ACMG points.

• PM1: In a helix (size 30) in uniprot entity ANDR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant X-67722944-G-A is Pathogenic according to our data. Variant chrX-67722944-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67722944-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2567G>A	p.Arg856His	missense_variant	Exon 7 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.971G>A	p.Arg324His	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.2567G>A	p.Arg856His	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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:4

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG:PM1 PM2 PP3 PP4 -

Jul 14, 2014

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 04, 2024

Genetics Department, Polish Mother's Memorial Hospital Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The patient is a 26-year-old phenotypically female with 46,XY karyotype, and typical symptoms of complete androgen insensitivity syndrome. The detected NM_000044.6: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 populational databases. The in-silico tool predicts a pathogenic outcome for this variant. In a UniProt entity ANDR_HUMAN, there are 26 pathogenic changes around, and none are benign. The variant has been reported in ClinVar as pathogenic (5 submissions) and likely pathogenic (1 submission). UniProt lists this variant as pathogenic. Another variant affecting the same amino acid position but resulting in a different missense (i.e., Arg856Cys) has been classified as pathogenic in ClinVar. The variant was classified as pathogenic with 10 ACMG points (criteria: PS4_moderate, PM1, PM2, PM5, PP3, PP4). -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Mar 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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"). 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9823). This variant is also known as R853H and 2926G>A (R855H). 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). This variant is not present in population databases (gnomAD no frequency). 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. -

Partial androgen insensitivity syndrome Pathogenic:1

Mar 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Male infertility Pathogenic:1

Jan 16, 2024

Institute of Reproductive Genetics, University of Münster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.90
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.98

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: rs9332971; hg19: chrX-66942786; COSMIC: COSV101018027;