X-67546285-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_000044.6(AR):c.1139C>G(p.Pro380Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,203,372 control chromosomes in the GnomAD database, including 2 homozygotes. There are 101 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., 55 hem., cov: 24)

Exomes 𝑓: 0.00019 ( 1 hom. 46 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

androgen insensitivity syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Kennedy disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
partial androgen insensitivity syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
complete androgen insensitivity syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

AR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.008013278).

BP6

Variant X-67546285-C-G is Benign according to our data. Variant chrX-67546285-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434263.

BS2

High Hemizygotes in GnomAd4 at 55 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1139C>G	p.Pro380Arg	missense_variant	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 link	c.1139C>G	p.Pro380Arg	missense_variant	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

205

AN:

112339

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00623

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000651

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:

0.0000188

Gnomad OTH

AF:

0.00266

GnomAD2 exomes

AF:

0.000563

AC:

AN:

159885

AF XY:

0.000291

show subpopulations

Gnomad AFR exome

AF:

0.00772

Gnomad AMR exome

AF:

0.000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

AF:

0.000189

AC:

206

AN:

1090981

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

357719

show subpopulations

African (AFR)

AF:

0.00609

AC:

160

AN:

26288

American (AMR)

AF:

0.000347

AC:

AN:

34562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19243

East Asian (EAS)

AF:

0.00

AC:

AN:

29904

South Asian (SAS)

AF:

0.00

AC:

AN:

53095

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

838977

Other (OTH)

AF:

0.000546

AC:

AN:

45789

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00182

AC:

205

AN:

112391

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

AN XY:

34575

show subpopulations

African (AFR)

AF:

0.00622

AC:

193

AN:

31041

American (AMR)

AF:

0.000650

AC:

AN:

10764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.00

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53110

Other (OTH)

AF:

0.00262

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000998

Hom.:

Bravo

AF:

0.00199

ESP6500AA

AF:

0.00632

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000531

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 27, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate reduced DHT-induced transactivation (Tadokoro-Cuccaro et al., 2014); Reported in individuals with partial androgen insensitivity syndrome (Audi et al., 2010; Bermejo-Costa et al., 2015); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25500996, 20150575, 26242926) -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AR-related disorder

Benign:1

Jun 02, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.;.;.;T;.

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

MetaRNN

Benign

0.0080

T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

PhyloP100

2.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.1

.;N;N;N;.;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

.;D;D;D;.;.

Sift4G

Benign

0.32

T;T;T;T;D;D

Vest4

0.72

MVP

0.94

MPC

0.94

ClinPred

0.041

GERP RS

5.1

Varity_R

0.28

gMVP

0.50

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over