rs886041133

chrX-67723746-G-AchrX-67723746-G-CchrX-67723746-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000044.6(AR):c.2668G>A(p.Val890Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V890L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.76

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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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-67723746-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338633.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant X-67723746-G-A is Pathogenic according to our data. Variant chrX-67723746-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67723746-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2668G>A	p.Val890Met	missense_variant	8/8	ENST00000374690.9
AR	NM_001011645.3	c.1072G>A	p.Val358Met	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2668G>A	p.Val890Met	missense_variant	8/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.*29G>A		3_prime_UTR_variant	5/5	1
AR	ENST00000396043.4	c.*1016G>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	1
AR	ENST00000612452.5	c.2668G>A	p.Val890Met	missense_variant, NMD_transcript_variant	8/9	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182688 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67360

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 8126121). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279690 / PMID: 10425033). A different missense change at the same codon (p.Val890Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430163, VCV001338633 / PMID: 20150575). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, however the androgen insensitivity (AIS) phenotype is known to only be caused by variants resulting in a loss-of-function (OMIM, PMID: 22334387). (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Minor amino acid change, very high conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternate change to leucine at the same residue has previously been reported as pathogenic in at least two patients with AIS (ClinVar, HGMD, PMID: 20150575). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with both complete and partial AIS (ClinVar, HGMD, PMID: 10425033, PMID: 24737579, PMID: 27051040). (P) 0903 - Low evidence for segregation with disease. The variant has previously been shown to segregate with AIS in at least one family (PMID: 29785970). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies of the variant in transfected cells demonstrated reduced androgen binding capacity (PMID: 8126121). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 890 of the AR protein (p.Val890Met). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AR function (PMID: 8126121). 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"). ClinVar contains an entry for this variant (Variation ID: 279690). This variant is also known as p.Val889Met and p.Val888Met. This missense change has been observed in individuals with complete androgen insensitivity syndrome (PMID: 10690872, 14974091, 15925895, 20150575, 24737579). This variant is present in population databases (no rsID available, gnomAD 0.008%). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2023

Published functional studies found this variant is associated with significant impairment of androgen binding capacity (de Bellis et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Missense variants in this gene are often considered pathogenic (HGMD); Also known as p.(V889M); This variant is associated with the following publications: (PMID: 29785970, 26522496, 14974091, 27802905, 10690872, 10425033, 20150575, 15925895, 27051040, 27022412, 33516834, 24737579, 8126121) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.77
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.89
MVP		1.0
MPC		1.2
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041133; hg19: chrX-66943588; COSMIC: COSV65955765;