rs137852572

Positions:

• chrX-67721838-G-A
• chrX-67721838-G-C
• chrX-67721838-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000044.6(AR):​c.2324G>A​(p.Arg775His) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant X-67721838-G-A is Pathogenic according to our data. Variant chrX-67721838-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67721838-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.2324G>A	p.Arg775His	missense_variant	6/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.728G>A	p.Arg243His	missense_variant	7/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2324G>A	p.Arg775His	missense_variant	6/8	1	NM_000044.6	ENSP00000363822	P1
AR	ENST00000396044.8	c.2174-1848G>A		intron_variant		1		ENSP00000379359
AR	ENST00000396043.4	c.*672G>A		3_prime_UTR_variant, NMD_transcript_variant	7/9	1		ENSP00000379358
AR	ENST00000612452.5	c.2324G>A	p.Arg775His	missense_variant, NMD_transcript_variant	6/9	5		ENSP00000484033

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 20, 2023	- -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg775 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1307250, 1609793, 8723113, 20150575). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects AR function (PMID: 1307250, 1480178, 1609793). 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: 9819). This missense change has been observed in individuals with androgen insensitivity syndrome (PMID: 1307250, 1609793, 8723113, 10690872, 20150575, 24737579, 25613104). 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 775 of the AR protein (p.Arg775His). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.070	T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.90
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.90

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: rs137852572; hg19: chrX-66941680; COSMIC: COSV65954067;