rs137852582

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The ENST00000374690.9(AR):​c.2708A>G​(p.Gln903Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q903K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 21)

Consequence

AR
ENST00000374690.9 missense

Scores

7
5
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000374690.9
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-67723785-C-A is described in Lovd as [Pathogenic].
PP5
Variant X-67723786-A-G is Pathogenic according to our data. Variant chrX-67723786-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9835.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-67723786-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARNM_000044.6 linkuse as main transcriptc.2708A>G p.Gln903Arg missense_variant 8/8 ENST00000374690.9 NP_000035.2
ARNM_001011645.3 linkuse as main transcriptc.1112A>G p.Gln371Arg missense_variant 9/9 NP_001011645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkuse as main transcriptc.2708A>G p.Gln903Arg missense_variant 8/81 NM_000044.6 ENSP00000363822 P1P10275-1
ARENST00000396044.8 linkuse as main transcriptc.*69A>G 3_prime_UTR_variant 5/51 ENSP00000379359
ARENST00000396043.4 linkuse as main transcriptc.*1056A>G 3_prime_UTR_variant, NMD_transcript_variant 9/91 ENSP00000379358
ARENST00000612452.5 linkuse as main transcriptc.2708A>G p.Gln903Arg missense_variant, NMD_transcript_variant 8/95 ENSP00000484033 P10275-1

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Prostate cancer, somatic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 25, 1995- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.64
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.042
T;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Uncertain
0.62
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.7
.;N;N
REVEL
Pathogenic
0.85
Sift
Uncertain
0.012
.;D;D
Sift4G
Benign
0.078
T;T;D
Vest4
0.61
MVP
1.0
MPC
1.3
ClinPred
0.96
D
GERP RS
5.2
Varity_R
0.88
gMVP
0.91

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: rs137852582; hg19: chrX-66943628; COSMIC: COSV65958490; API