rs137852564

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

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. V867E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.18

Variant links:

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]

AR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 30) in uniprot entity ANDR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

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 rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.2599G>A	p.Val867Met	missense_variant	Exon 7 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3 link	c.1003G>A	p.Val335Met	missense_variant	Exon 8 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 link	c.2599G>A	p.Val867Met	missense_variant	Exon 7 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098026

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363436

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Androgen resistance syndrome

Pathogenic:3

Dec 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 05, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Androgen resistance syndrome;C1839259:Kennedy disease

Pathogenic:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 867 of the AR protein (p.Val867Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with partial androgen insensitivity syndrome (PMID: 2594783, 26688387, 26806084). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val866Met. ClinVar contains an entry for this variant (Variation ID: 9806). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AR function (PMID: 27583472). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AR-related disorder

Pathogenic:1

Jan 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Benign

0.19

DEOGEN2

Benign

0.0095

T;.;.

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.47

.;N;N

REVEL

Uncertain

0.64

Sift

Benign

0.64

.;T;T

Sift4G

Benign

0.38

T;T;T

Vest4

0.77

MVP

0.99

MPC

1.2

ClinPred

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over