X-67545280-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_000044.6(AR):c.134C>G(p.Ala45Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,202,960 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 4 hem., cov: 20)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.315

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 -9 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=0.012919277).

BP6

Variant X-67545280-C-G is Benign according to our data. Variant chrX-67545280-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 733466.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.134C>G	p.Ala45Gly	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.134C>G	p.Ala45Gly	missense_variant	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.000271

AC:

AN:

106897

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000987

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000332

AC:

AN:

180840

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.000474

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1096040

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362222

show subpopulations

African (AFR)

AF:

0.000532

AC:

AN:

26323

American (AMR)

AF:

0.00

AC:

AN:

35091

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19316

East Asian (EAS)

AF:

0.00

AC:

AN:

30017

South Asian (SAS)

AF:

0.00

AC:

AN:

53995

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40329

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3739

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841304

Other (OTH)

AF:

0.00

AC:

AN:

45926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000262

AC:

AN:

106920

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

29660

show subpopulations

African (AFR)

AF:

0.000951

AC:

AN:

29435

American (AMR)

AF:

0.00

AC:

AN:

10012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2574

East Asian (EAS)

AF:

0.00

AC:

AN:

3303

South Asian (SAS)

AF:

0.00

AC:

AN:

2297

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51713

Other (OTH)

AF:

0.00

AC:

AN:

1425

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000336

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

.;.;.;T;.

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.63

T;T;T;T;T

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.76

.;N;N;.;.

PhyloP100

-0.32

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.95

N;N;N;.;.

REVEL

Benign

0.071

Sift

Benign

0.15

T;T;T;.;.

Sift4G

Benign

0.20

T;T;T;T;T

Vest4

0.11

MVP

0.53

MPC

0.40

ClinPred

0.015

GERP RS

1.4

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.097

gMVP

0.62

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-67545280-C-G

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