rs137852589

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000044.6(AR):​c.2343G>A​(p.Met781Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

AR
NM_000044.6 missense

Scores

9
2
5

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant X-67721857-G-A is Pathogenic according to our data. Variant chrX-67721857-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 492796.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67721857-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARNM_000044.6 linkc.2343G>A p.Met781Ile missense_variant 6/8 ENST00000374690.9 NP_000035.2
ARNM_001011645.3 linkc.747G>A p.Met249Ile missense_variant 7/9 NP_001011645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkc.2343G>A p.Met781Ile missense_variant 6/81 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.00000546
AC:
1
AN:
183232
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67746
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
9.11e-7
AC:
1
AN:
1097957
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363341
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 03, 2024Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(M780I); This variant is associated with the following publications: (PMID: 7626493, 1458719, 8990010, 1307250, 8824883, 15531547, 11549642, 17054461, 26778393, 8768864, 19125473, 16930995, 31012339, 10323251) -
Androgen resistance syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMar 23, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.67
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.063
T;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.67
T;T;T
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.91
D;D;D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-3.1
.;D;D
REVEL
Pathogenic
0.94
Sift
Benign
0.051
.;T;T
Sift4G
Benign
0.064
T;T;T
Vest4
0.91
MVP
1.0
MPC
1.2
ClinPred
0.80
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852589; hg19: chrX-66941699; API