rs150226204

Positions:

• chrX-67545782-G-A
• chrX-67545782-G-C
• chrX-67545782-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_000044.6(AR):​c.636G>A​(p.Arg212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,210,606 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,498 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., 73 hem., cov: 22)
  • Exomes 𝑓: 0.0033 (9 hom. 1425 hem.)
• Consequence: AR NM_000044.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.672

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=0.672 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00329 (3617/1097937) while in subpopulation SAS AF= 0.0179 (969/54085). AF 95% confidence interval is 0.017. There are 9 homozygotes in gnomad4_exome. There are 1425 alleles in male gnomad4_exome subpopulation. Median coverage is 56. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 73 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.636G>A	p.Arg212=	synonymous_variant	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.636G>A	p.Arg212=	synonymous_variant	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 232 AN: 112613 Hom.: 1 Cov.: 22 AF XY: 0.00210 AC XY: 73 AN XY: 34769

Gnomad AFR AF: 0.000548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00233

Gnomad ASJ AF: 0.00263

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.000160

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00242

Gnomad OTH AF: 0.00330

GnomAD3 exomes AF: 0.00367 AC: 667 AN: 181906 Hom.: 1 AF XY: 0.00464 AC XY: 309 AN XY: 66526

Gnomad AFR exome AF: 0.000927

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00329 AC: 3617 AN: 1097937 Hom.: 9 Cov.: 56 AF XY: 0.00392 AC XY: 1425 AN XY: 363311

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.0000994

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00206 AC: 232 AN: 112669 Hom.: 1 Cov.: 22 AF XY: 0.00210 AC XY: 73 AN XY: 34835

Gnomad4 AFR AF: 0.000547

Gnomad4 AMR AF: 0.00232

Gnomad4 ASJ AF: 0.00263

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0171

Gnomad4 FIN AF: 0.000160

Gnomad4 NFE AF: 0.00242

Gnomad4 OTH AF: 0.00326

Alfa AF: 0.00261 Hom.: 17

Bravo AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.0
DANN	Benign	0.87

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: rs150226204; hg19: chrX-66765624;