Genetic Variant AR:p.Ala871Val (chrX-67723690-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 13P and 5B. PM1PM5PP2PP5_Very_StrongBP4BS2

The NM_000044.6(AR):c.2612C>T(p.Ala871Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,207,648 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A871E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000018 ( 0 hom. 8 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.66

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, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
Kennedy disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
partial androgen insensitivity syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
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_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000044.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-67723690-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3759649.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP5

Variant X-67723690-C-T is Pathogenic according to our data. Variant chrX-67723690-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 492801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.33267808). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAdExome4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.2612C>T	p.Ala871Val	missense	Exon 8 of 8	NP_000035.2
	AR	NM_001011645.3		c.1016C>T	p.Ala339Val	missense	Exon 9 of 9	NP_001011645.1	Q9NUA2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AR	ENST00000374690.9	TSL:1 MANE Select	c.2612C>T	p.Ala871Val	missense	Exon 8 of 8	ENSP00000363822.3	P10275-1
AR	ENST00000396044.8	TSL:1	c.2178C>T	p.Cys726Cys	synonymous	Exon 5 of 5	ENSP00000379359.3	F5GZG9
AR	ENST00000396043.4	TSL:1	n.*960C>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000379358.4	A0A7I2PS51

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

109992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000331

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181154

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000152

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:

0.0000182

AC:

AN:

1097656

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363072

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26388

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

841712

Other (OTH)

AF:

0.0000217

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000182

AC:

AN:

109992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32276

show subpopulations

African (AFR)

AF:

0.0000331

AC:

AN:

30189

American (AMR)

AF:

0.00

AC:

AN:

10376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3390

South Asian (SAS)

AF:

0.00

AC:

AN:

2444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52711

Other (OTH)

AF:

0.00

AC:

AN:

1458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Androgen resistance syndrome (4)

not provided (2)

Androgen resistance syndrome;C1839259:Kennedy disease (1)

Differences in sex development (1)

Hypospadias 1, X-linked (1)

Partial androgen insensitivity syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.0050

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.33

MetaSVM

Pathogenic

0.90

PhyloP100

4.7

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.77

REVEL

Uncertain

0.62

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.68

MVP

0.98

MPC

0.92

ClinPred

0.20

GERP RS

5.2

Varity_R

0.51

gMVP

0.87

Mutation Taster

=6/94

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

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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

Computational scores

Splicing

Publications

Other links and lift over