rs137852564

chrX-67722976-G-AchrX-67722976-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000044.6(AR):c.2599G>A(p.Val867Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,026 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign 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. V867L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.18

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 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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-67722976-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9822.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant X-67722976-G-A is Pathogenic according to our data. Variant chrX-67722976-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67722976-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39299953).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2599G>A	p.Val867Met	missense_variant	7/8	ENST00000374690.9
AR	NM_001011645.3	c.1003G>A	p.Val335Met	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2599G>A	p.Val867Met	missense_variant	7/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2174-710G>A		intron_variant		1
AR	ENST00000396043.4	c.*947G>A		3_prime_UTR_variant, NMD_transcript_variant	8/9	1
AR	ENST00000612452.5	c.2599G>A	p.Val867Met	missense_variant, NMD_transcript_variant	7/9	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098026 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Aug 05, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1989	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 18, 2020	A homozygous missense variation in exon 7 of the AR gene that results in amino acid substitution of methionine for valine at codon 867 was detected. The observed variant c.2599G>A has not been reported in the 1000 genomes and ExAC databases. The variant lies in the ligand-binding domain of nuclear hormone receptor domain of the AR protein and has previously been reported as p.Val866Met in patients affected with androgen insensitivity (Lubahn et al. 1989). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

AR-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2023

The AR c.2599G>A variant is predicted to result in the amino acid substitution p.Val867Met. This variant, also known as p.Val866Met, has been reported in multiple individuals with androgen insensitivity syndrome (Lubahn et al 1989. PubMed ID: 2594783; Abilash et al. 2016. PubMed ID: 26688387; Li L et al 2017. PubMed ID: 26806084; Suppl. Table 1, Eggers S et al 2016. PubMed ID: 27899157). This variant lies in the ligand-binding domain of the androgen receptor protein. Functional studies show that this variant reduces dihydrotestosterone (DHT)-dependent, AR-induced transcriptional activation (Horing et al. 2016. PubMed ID: 27583472). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2020

This sequence change replaces valine with methionine at codon 867 of the AR protein (p.Val867Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant is located in the ligand binding domain of the androgen receptor(AR) protein and experimental evidence using genital fibroblast cultures shows this variant has reduced dihydrotestosterone(DHT)-dependent, AR-induced transcriptional activation (PMID: 27583472). This variant has been reported in individuals and families affected with partial androgen insensitivity syndrome (PMID: 2594783, 26806084, 26688387). This variant is also known as p.Val866Met. ClinVar contains an entry for this variant (Variation ID: 9806). -

Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome;C0376358:Malignant tumor of prostate;C1839259:Kennedy disease;C2678098:Hypospadias 1, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	23
Dann	Benign	0.19
DEOGEN2	Benign	0.0095	T;.;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.38	T;T;T
Vest4		0.77
MVP		0.99
MPC		1.2
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.82

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: rs137852564; hg19: chrX-66942818; COSMIC: COSV65954254;