rs1337075

Variant names:

• chrX-67689581-C-T
• rs1337075
• ENST00000513847.5:n.2238C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000513847.5(AR):​n.2238C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 962,744 control chromosomes in the GnomAD database, including 836 homozygotes. There are 2,933 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.058 (477 hom., 1681 hem., cov: 23)
  • Exomes 𝑓: 0.0057 (359 hom. 1252 hem.)
• Consequence: AR ENST00000513847.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1885+3455C>T		intron_variant	Intron 3 of 7	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1885+3455C>T		intron_variant	Intron 3 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0579 AC: 6404 AN: 110631 Hom.: 477 Cov.: 23

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000781

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0297

Gnomad NFE AF: 0.000699

Gnomad OTH AF: 0.0518

GnomAD2 exomes AF: 0.0109 AC: 946 AN: 86730 AF XY: 0.00499

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.00754

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00567 AC: 4827 AN: 852062 Hom.: 359 Cov.: 28 AF XY: 0.00458 AC XY: 1252 AN XY: 273604

African (AFR) AF: 0.211 AC: 3997 AN: 18905

American (AMR) AF: 0.00926 AC: 202 AN: 21807

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 13 AN: 11752

East Asian (EAS) AF: 0.00 AC: 0 AN: 9403

South Asian (SAS) AF: 0.000434 AC: 20 AN: 46058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9467

Middle Eastern (MID) AF: 0.0102 AC: 32 AN: 3152

European-Non Finnish (NFE) AF: 0.000291 AC: 204 AN: 700029

Other (OTH) AF: 0.0114 AC: 359 AN: 31489

GnomAD4 genome AF: 0.0579 AC: 6414 AN: 110682 Hom.: 477 Cov.: 23 AF XY: 0.0509 AC XY: 1681 AN XY: 33010

African (AFR) AF: 0.200 AC: 6075 AN: 30326

American (AMR) AF: 0.0209 AC: 216 AN: 10359

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3491

South Asian (SAS) AF: 0.000392 AC: 1 AN: 2550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5981

Middle Eastern (MID) AF: 0.0326 AC: 7 AN: 215

European-Non Finnish (NFE) AF: 0.000681 AC: 36 AN: 52901

Other (OTH) AF: 0.0511 AC: 78 AN: 1525

Alfa AF: 0.0299 Hom.: 177

Bravo AF: 0.0668

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.69
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs1337075; hg19: chrX-66909423;