rs12011518

Positions:

• chrX-67713194-G-T

Variant summary

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

The NM_000044.6(AR):​c.2173+1505G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 110,354 control chromosomes in the GnomAD database, including 263 homozygotes. There are 2,166 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 0.078 (263 hom., 2166 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2173+1505G>T		intron_variant		ENST00000374690.9
AR	NM_001011645.3	c.577+1505G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2173+1505G>T		intron_variant		1	NM_000044.6	P1
AR	ENST00000396044.8	c.2173+1505G>T		intron_variant		1
AR	ENST00000396043.4	c.*521+1505G>T		intron_variant, NMD_transcript_variant		1
AR	ENST00000612452.5	c.2173+1505G>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 8581 AN: 110303 Hom.: 262 Cov.: 22 AF XY: 0.0664 AC XY: 2163 AN XY: 32551

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.0190

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0944

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0980

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0778 AC: 8590 AN: 110354 Hom.: 263 Cov.: 22 AF XY: 0.0664 AC XY: 2166 AN XY: 32612

Gnomad4 AFR AF: 0.0995

Gnomad4 AMR AF: 0.0634

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0225

Gnomad4 FIN AF: 0.0500

Gnomad4 NFE AF: 0.0800

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.0802 Hom.: 2539

Bravo AF: 0.0807

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.58

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: rs12011518; hg19: chrX-66933036;