rs5031002

Positions:

• chrX-67722783-G-A
• chrX-67722783-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000044.6(AR):​c.2450-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,198,668 control chromosomes in the GnomAD database, including 229 homozygotes. There are 8,357 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (12 hom., 426 hem., cov: 22)
  • Exomes 𝑓: 0.023 (217 hom. 7931 hem.)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.184

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (1612/111198) while in subpopulation NFE AF= 0.0247 (1307/52985). AF 95% confidence interval is 0.0236. There are 12 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2450-44G>A		intron_variant		ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.854-44G>A		intron_variant			NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2450-44G>A		intron_variant		1	NM_000044.6	ENSP00000363822	P1
AR	ENST00000396044.8	c.2174-903G>A		intron_variant		1		ENSP00000379359
AR	ENST00000396043.4	c.*798-44G>A		intron_variant, NMD_transcript_variant		1		ENSP00000379358
AR	ENST00000612452.5	c.2450-44G>A		intron_variant, NMD_transcript_variant		5		ENSP00000484033

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 1613 AN: 111144 Hom.: 12 Cov.: 22 AF XY: 0.0128 AC XY: 427 AN XY: 33370

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00291

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00342

Gnomad EAS AF: 0.000285

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.00736

GnomAD3 exomes AF: 0.0146 AC: 2561 AN: 175518 Hom.: 10 AF XY: 0.0140 AC XY: 858 AN XY: 61162

Gnomad AFR exome AF: 0.00322

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00694

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0230 AC: 24994 AN: 1087470 Hom.: 217 Cov.: 29 AF XY: 0.0224 AC XY: 7931 AN XY: 354226

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.00285

Gnomad4 EAS exome AF: 0.0000668

Gnomad4 SAS exome AF: 0.00850

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0145 AC: 1612 AN: 111198 Hom.: 12 Cov.: 22 AF XY: 0.0127 AC XY: 426 AN XY: 33434

Gnomad4 AFR AF: 0.00357

Gnomad4 AMR AF: 0.00609

Gnomad4 ASJ AF: 0.00342

Gnomad4 EAS AF: 0.000286

Gnomad4 SAS AF: 0.00460

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.00728

Alfa AF: 0.0226 Hom.: 1465

Bravo AF: 0.0131

ClinVar

Significance: Benign

Submissions summary: Benign:3

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: 27884173, 20150575) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.0
DANN	Benign	0.64

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: rs5031002; hg19: chrX-66942625; COSMIC: COSV65964902;