X-67723690-C-T

Position:

chrX-67723690-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4

The NM_000044.6(AR):c.2612C>T(p.Ala871Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,207,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes 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. A871G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000018 ( 0 hom. 8 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.66

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 11 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

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-67723690-C-T is Pathogenic according to our data. Variant chrX-67723690-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 492801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67723690-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.33267808). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6 linkuse as main transcript	c.2612C>T	p.Ala871Val	missense_variant	8/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3 linkuse as main transcript	c.1016C>T	p.Ala339Val	missense_variant	9/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 linkuse as main transcript	c.2612C>T	p.Ala871Val	missense_variant	8/8	1	NM_000044.6	ENSP00000363822	P1	P10275-1
AR	ENST00000396044.8 linkuse as main transcript	c.2178C>T	p.Cys726=	synonymous_variant	5/5	1		ENSP00000379359
AR	ENST00000396043.4 linkuse as main transcript	c.*960C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	1		ENSP00000379358
AR	ENST00000612452.5 linkuse as main transcript	c.2612C>T	p.Ala871Val	missense_variant, NMD_transcript_variant	8/9	5		ENSP00000484033		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

109992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32276

show subpopulations

Gnomad AFR

AF:

0.0000331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181154

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66882

show subpopulations

Gnomad AFR exome

AF:

0.000152

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

AF:

0.0000182

AC:

AN:

1097656

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363072

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000247

Gnomad4 NFE exome

AF:

0.0000202

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000182

AC:

AN:

109992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32276

show subpopulations

Gnomad4 AFR

AF:

0.0000331

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Androgen resistance syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with androgen insensitivity (MIM#300068), androgen insensitivity, partial, with or without breast cancer (MIM#312300), hypospadias 1, X-linked (MIM#300633), or spinal and bulbar muscular atrophy of Kennedy (MIM#313200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ligand-binding domain of nuclear hormone receptor (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been reported in several individuals with 46,XY differences of sex development in the literature (PMIDs: 8033918, 28261839, 34689141, 27051040). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 21, 2023	Criteria applied: PS4,PM5_STR,PM1,PM2_SUP,PP3,PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Sep 05, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2023	Variant summary: AR c.2612C>T (p.Ala871Val) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 181154 control chromosomes (i.e, 2 heterozygous female carriers; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2612C>T has been reported in the literature in multiple hemizygous males affected with Androgen Resistance Syndrome (e.g., Hiort_1994, Hiort_1996, Bhangoo_2010, Zhang_2019, Kumar_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20305676, 8723113, 8033918, 34689141, 31219235). Four ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 03, 2021	DNA sequence analysis of the AR gene demonstrated a sequence change, c.2612C>T, in exon 8 that results in an amino acid change, p.Ala871Val. The p.Ala871Val change affects a moderately conserved amino acid residue located in the ligand binding domain of the AR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala871Val substitution. This sequence change has been described in the gnomAD database in the heterozygous state in two individuals which corresponds to a population frequency of 0.0011% (dbSNP rs143040492). This pathogenic sequence change has previously been described in multiple individuals with AR-related disorders (PMID: 31219235, 8033918, 28261839, 20305676, 8723113). Additionally, other variants impacting this same amino acid residue, p.Ala871Gly and p.Ala871Glu, have been reported in individuals with AR-related disorders (PMID: 7981687, 9332480). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively. -

Androgen resistance syndrome;C1839259:Kennedy disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 871 of the AR protein (p.Ala871Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with androgen insensitivity syndrome (PMID: 8033918, 8723113, 20305676, 28261839). This variant is also known as p.Ala870Val. ClinVar contains an entry for this variant (Variation ID: 492801). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ala871 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (PMID: 7981687, 8723113, 9332480), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Hypospadias 1, X-linked

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Apr 17, 2023

This variant has been identified by standard clinical testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Benign

0.31

DEOGEN2

Benign

0.0050

T;.;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.77

.;N;N

REVEL

Uncertain

0.62

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Vest4

0.68

MVP

0.98

MPC

0.92

ClinPred

0.20

GERP RS

5.2

Varity_R

0.51

gMVP

0.87

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