rs764238988

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_000044.6(AR):c.1513C>A(p.Pro505Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000457 in 1,203,937 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 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., 3 hem., cov: 21)

Exomes 𝑓: 0.000047 ( 0 hom. 21 hem. )

Consequence

AR
NM_000044.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 1.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5

Variant X-67546659-C-A is Pathogenic according to our data. Variant chrX-67546659-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522694.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chrX-67546659-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.24932534). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAd4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6 linkuse as main transcript	c.1513C>A	p.Pro505Thr	missense_variant	1/8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 linkuse as main transcript	c.1513C>A	p.Pro505Thr	missense_variant	1/8	1	NM_000044.6	ENSP00000363822	P1	P10275-1

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

110512

Hom.:

Cov.:

AF XY:

0.0000915

AC XY:

AN XY:

32796

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:

0.00

Gnomad SAS

AF:

0.000770

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000413

AC:

AN:

169537

Hom.:

AF XY:

0.0000355

AC XY:

AN XY:

56399

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.000235

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1093383

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

359445

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000113

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000488

Gnomad4 OTH exome

AF:

0.0000654

GnomAD4 genome

AF:

0.0000362

AC:

AN:

110554

Hom.:

Cov.:

AF XY:

0.0000913

AC XY:

AN XY:

32848

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000773

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000380

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000907

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Male infertility

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

in vitro;research

Institute of Reproductive Genetics, University of Münster

Jan 16, 2024

- -

Androgen resistance syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;.;T;.

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.25

T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

.;D;D;D;.;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

.;D;D;D;.;.

Sift4G

Uncertain

0.0070

D;D;D;D;D;D

Vest4

0.16

MVP

1.0

MPC

1.3

ClinPred

0.65

GERP RS

5.1

Varity_R

0.67

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over