rs6152

Positions:

• chrX-67545785-G-A
• chrX-67545785-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000044.6(AR):​c.639G>A​(p.Glu213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,209,546 control chromosomes in the GnomAD database, including 16,446 homozygotes. There are 62,319 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (4860 hom., 8618 hem., cov: 23)
  • Exomes 𝑓: 0.15 (11586 hom. 53701 hem.)
• Consequence: AR NM_000044.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-67545785-G-A is Benign according to our data. Variant chrX-67545785-G-A is described in ClinVar as [Benign]. Clinvar id is 155758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67545785-G-A is described in Lovd as [Benign]. Variant chrX-67545785-G-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.639G>A	p.Glu213=	synonymous_variant	1/8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.639G>A	p.Glu213=	synonymous_variant	1/8	1	NM_000044.6	ENSP00000363822	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 30456 AN: 111940 Hom.: 4860 Cov.: 23 AF XY: 0.251 AC XY: 8583 AN XY: 34128

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00169

Gnomad SAS AF: 0.0799

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.238

GnomAD3 exomes AF: 0.152 AC: 27505 AN: 181185 Hom.: 2808 AF XY: 0.135 AC XY: 8911 AN XY: 65899

Gnomad AFR exome AF: 0.622

Gnomad AMR exome AF: 0.0765

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.000724

Gnomad SAS exome AF: 0.0886

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.152 AC: 166871 AN: 1097551 Hom.: 11586 Cov.: 59 AF XY: 0.148 AC XY: 53701 AN XY: 362953

Gnomad4 AFR exome AF: 0.626

Gnomad4 AMR exome AF: 0.0851

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.000629

Gnomad4 SAS exome AF: 0.0893

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.272 AC: 30495 AN: 111995 Hom.: 4860 Cov.: 23 AF XY: 0.252 AC XY: 8618 AN XY: 34193

Gnomad4 AFR AF: 0.615

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.00170

Gnomad4 SAS AF: 0.0802

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.236

Alfa AF: 0.192 Hom.: 2201

Bravo AF: 0.285

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25241384, 19167832, 15824176, 11231320) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Androgen resistance syndrome Benign:1

Benign, no assertion criteria provided

literature only

GeneReviews

Jul 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.83

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

Other links and lift over

dbSNP: rs6152; hg19: chrX-66765627; COSMIC: COSV65952836;