Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_ModerateBP6_Moderate

The NM_000044.6(AR):c.421G>A(p.Ala141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,069,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 22)

Exomes 𝑓: 0.0000028 ( 0 hom. 0 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.334

Publications

1 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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.073743165).

BP6

Variant X-67545567-G-A is Benign according to our data. Variant chrX-67545567-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 434258.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AR	NM_000044.6	MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 8	NP_000035.2
AR	NM_001348063.1		c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	NP_001334992.1
AR	NM_001348061.1		c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	NP_001334990.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AR	ENST00000374690.9	TSL:1 MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 8	ENSP00000363822.3
AR	ENST00000396044.8	TSL:1	c.421G>A	p.Ala141Thr	missense	Exon 1 of 5	ENSP00000379359.3
AR	ENST00000504326.5	TSL:1	c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000230

AC:

AN:

130472

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000136

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:

0.00000280

AC:

AN:

1069951

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

347505

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25816

American (AMR)

AF:

0.0000973

AC:

AN:

30827

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18812

East Asian (EAS)

AF:

0.00

AC:

AN:

28677

South Asian (SAS)

AF:

0.00

AC:

AN:

51072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37993

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

827761

Other (OTH)

AF:

0.00

AC:

AN:

45003

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0099

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.44

PhyloP100

-0.33

PrimateAI

Benign

0.46

PROVEAN

Benign

0.35

REVEL

Benign

0.14

Sift

Benign

0.58

Sift4G

Benign

0.57

Vest4

0.053

MVP

0.77

MPC

0.39

ClinPred

0.016

GERP RS

0.22

PromoterAI

-0.075

Neutral

(source)

Varity_R

0.042

gMVP

0.34

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.

NM_000044.6:c.421G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over