rs1800053

chrX-67711453-C-AchrX-67711453-C-GchrX-67711453-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000044.6(AR):c.1937C>A(p.Ala646Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,202,319 control chromosomes in the GnomAD database, including 2 homozygotes. There are 764 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 37 hem., cov: 23)

Exomes 𝑓: 0.0021 ( 2 hom. 727 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:7

Conservation

PhyloP100: 0.405

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17819354).

BS2

High Hemizygotes in GnomAd at 37 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6 linkuse as main transcript	c.1937C>A	p.Ala646Asp	missense_variant	4/8	ENST00000374690.9
AR	NM_001011645.3 linkuse as main transcript	c.341C>A	p.Ala114Asp	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9 linkuse as main transcript	c.1937C>A	p.Ala646Asp	missense_variant	4/8	1	NM_000044.6	P1	P10275-1
AR	ENST00000396044.8 linkuse as main transcript	c.1937C>A	p.Ala646Asp	missense_variant	4/5	1
AR	ENST00000396043.4 linkuse as main transcript	c.*285C>A		3_prime_UTR_variant, NMD_transcript_variant	5/9	1
AR	ENST00000612452.5 linkuse as main transcript	c.1937C>A	p.Ala646Asp	missense_variant, NMD_transcript_variant	4/9	5			P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

135

AN:

112131

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

34299

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00113

AC:

185

AN:

163917

Hom.:

AF XY:

0.00112

AC XY:

AN XY:

51987

show subpopulations

Gnomad AFR exome

AF:

0.000168

Gnomad AMR exome

AF:

0.000155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000408

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.00214

AC:

2333

AN:

1090188

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

727

AN XY:

357196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000761

Gnomad4 AMR exome

AF:

0.000146

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000450

Gnomad4 NFE exome

AF:

0.00269

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00120

AC:

135

AN:

112131

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

34299

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00121

AC:

146

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	AR: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Partial androgen insensitivity syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Castleman-Kojima disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Aug 12, 2019

- -

Male infertility

Uncertain:1

Uncertain significance, criteria provided, single submitter

in vitro;research

Institute of Reproductive Genetics, University of Münster

Jan 16, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

AR-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.0068

T;.;.;.

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.57

MutationTaster

Benign

0.030

A;A;A

PrimateAI

Benign

0.34

Sift4G

Benign

0.56

T;T;T;T

Vest4

0.70

MVP

0.96

MPC

0.68

ClinPred

0.0084

GERP RS

1.3

Varity_R

0.13

gMVP

0.61

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