chrX-67545785-G-A

Variant names:

• chrX-67545785-G-A
• rs6152
• NM_000044.6:c.639G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000044.6(AR):​c.639G>A​(p.Glu213Glu) 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
• Publications: 68 publications found

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, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 155758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 4	NP_001334992.1
	AR	NM_001348061.1		c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 4	NP_001334990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 5	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.639G>A	p.Glu213Glu	synonymous	Exon 1 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 30456 AN: 111940 Hom.: 4860 Cov.: 23

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

GnomAD2 exomes AF: 0.152 AC: 27505 AN: 181185 AF XY: 0.135

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 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

African (AFR) AF: 0.626 AC: 16531 AN: 26387

American (AMR) AF: 0.0851 AC: 2994 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 2372 AN: 19381

East Asian (EAS) AF: 0.000629 AC: 19 AN: 30193

South Asian (SAS) AF: 0.0893 AC: 4833 AN: 54092

European-Finnish (FIN) AF: 0.132 AC: 5349 AN: 40476

Middle Eastern (MID) AF: 0.181 AC: 747 AN: 4137

European-Non Finnish (NFE) AF: 0.150 AC: 126550 AN: 841659

Other (OTH) AF: 0.162 AC: 7476 AN: 46062

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

African (AFR) AF: 0.615 AC: 18880 AN: 30714

American (AMR) AF: 0.142 AC: 1520 AN: 10707

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 304 AN: 2655

East Asian (EAS) AF: 0.00170 AC: 6 AN: 3530

South Asian (SAS) AF: 0.0802 AC: 215 AN: 2682

European-Finnish (FIN) AF: 0.116 AC: 714 AN: 6166

Middle Eastern (MID) AF: 0.188 AC: 41 AN: 218

European-Non Finnish (NFE) AF: 0.158 AC: 8372 AN: 53126

Other (OTH) AF: 0.236 AC: 358 AN: 1518

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25241384, 19167832, 15824176, 11231320)

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Androgen resistance syndrome Benign:1

Jul 10, 2014

GeneReviews

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.83
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6152; hg19: chrX-66765627;