rs1337075

chrX-67689581-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000044.6(AR):c.1885+3455C>T variant causes a intron 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 NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88

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=-0.89).
• 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/exons	MANE	UniProt
AR	NM_000044.6	c.1885+3455C>T		intron_variant		ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1885+3455C>T		intron_variant		1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.0579 AC: 6404 AN: 110631 Hom.: 477 Cov.: 23 AF XY: 0.0508 AC XY: 1675 AN XY: 32949

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

GnomAD3 exomes AF: 0.0109 AC: 946 AN: 86730 Hom.: 74 AF XY: 0.00499 AC XY: 146 AN XY: 29246

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 SAS exome AF: 0.000401

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

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000434

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.0114

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

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000392

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000681

Gnomad4 OTH AF: 0.0511

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

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: rs1337075; hg19: chrX-66909423;