X-67717535-G-T

Variant names:

• chrX-67717535-G-T
• rs137852600
• NM_000044.6:c.2231G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000044.6(AR):​c.2231G>T​(p.Gly744Val) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.71

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 10 ACMG points.

• PM1: In a helix (size 27) in uniprot entity ANDR_HUMAN there are 18 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, 0.968
• PP5: Variant X-67717535-G-T is Pathogenic according to our data. Variant chrX-67717535-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717535-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2231G>T	p.Gly744Val	missense_variant	Exon 5 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.635G>T	p.Gly212Val	missense_variant	Exon 6 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2231G>T	p.Gly744Val	missense_variant	Exon 5 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Feb 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects AR protein function (PMID: 8325932, 9768671). This variant has been observed in individual(s) with androgen insensitivity syndrome (PMID: 8096390, 8325932, 9768671). In at least one individual the variant was observed to be de novo. This variant is also known as Gly743Val. ClinVar contains an entry for this variant (Variation ID: 9857). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 744 of the AR protein (p.Gly744Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. -

Partial androgen insensitivity syndrome Pathogenic:1

Jul 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Androgen resistance syndrome Pathogenic:1

Jul 01, 1993

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	0.75
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	.;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0080	.;D;T
Sift4G	Uncertain	0.045	D;D;T
Vest4		0.93
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.96

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: rs137852600; hg19: chrX-66937377; COSMIC: COSV65962889;