rs137852565

chrX-67721905-G-AchrX-67721905-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000044.6(AR):c.2391G>A(p.Trp797Ter) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.77

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-67721905-G-A is Pathogenic according to our data. Variant chrX-67721905-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9807.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67721905-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2391G>A	p.Trp797Ter	stop_gained	6/8	ENST00000374690.9
AR	NM_001011645.3	c.795G>A	p.Trp265Ter	stop_gained	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2391G>A	p.Trp797Ter	stop_gained	6/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2174-1781G>A		intron_variant		1
AR	ENST00000396043.4	c.*739G>A		3_prime_UTR_variant, NMD_transcript_variant	7/9	1
AR	ENST00000612452.5	c.2391G>A	p.Trp797Ter	stop_gained, NMD_transcript_variant	6/9	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 07, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in AR are known to be pathogenic (PMID: 19463997). This variant has been reported in several individuals affected with complete androgen insensitivity syndrome (PMID: 2332504, 25613104). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp797*) in the AR gene. It is expected to result in an absent or disrupted protein product. -

Androgen resistance syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	39
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.96
GERP RS		4.8

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: rs137852565; hg19: chrX-66941747; COSMIC: COSV65954641;