rs137852571

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000044.6(AR):c.2191G>A(p.Val731Met) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,210,381 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000023 ( 0 hom. 11 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.27

Publications

9 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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000044.6

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=0.21336913).

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.2191G>A	p.Val731Met	missense	Exon 5 of 8	NP_000035.2
	AR	NM_001011645.3		c.595G>A	p.Val199Met	missense	Exon 6 of 9	NP_001011645.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AR	ENST00000374690.9	TSL:1 MANE Select	c.2191G>A	p.Val731Met	missense	Exon 5 of 8	ENSP00000363822.3
AR	ENST00000396043.4	TSL:1	n.*539G>A		non_coding_transcript_exon	Exon 6 of 9	ENSP00000379358.4
AR	ENST00000396043.4	TSL:1	n.*539G>A		3_prime_UTR	Exon 6 of 9	ENSP00000379358.4

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112311

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000842

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000766

AC:

AN:

182820

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1098018

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363412

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.000232

AC:

AN:

30175

South Asian (SAS)

AF:

0.000111

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

842047

Other (OTH)

AF:

0.000130

AC:

AN:

46079

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000356

AC:

AN:

112363

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34543

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30932

American (AMR)

AF:

0.00

AC:

AN:

10681

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.000845

AC:

AN:

3550

South Asian (SAS)

AF:

0.000371

AC:

AN:

2697

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53262

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Androgen resistance syndrome;C1839259:Kennedy disease (1)

Prostate cancer (1)

Prostate cancer, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.0052

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

0.99

PhyloP100

4.3

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.76

Sift

Uncertain

0.011

Sift4G

Uncertain

0.042

Vest4

0.71

MVP

0.98

MPC

0.46

ClinPred

0.083

GERP RS

5.0

Varity_R

0.78

gMVP

0.87

Mutation Taster

=59/41

disease causing (ClinVar)

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over