rs12011518

Variant names:

• chrX-67713194-G-T
• rs12011518
• NM_000044.6:c.2173+1505G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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=-0.85).
• 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 rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2173+1505G>T		intron_variant	Intron 4 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.577+1505G>T		intron_variant	Intron 5 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2173+1505G>T		intron_variant	Intron 4 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2173+1505G>T		intron_variant	Intron 4 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*521+1505G>T		intron_variant	Intron 5 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.2173+1505G>T		intron_variant	Intron 4 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 8581 AN: 110303 Hom.: 262 Cov.: 22

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

African (AFR) AF: 0.0995 AC: 3016 AN: 30300

American (AMR) AF: 0.0634 AC: 652 AN: 10280

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 163 AN: 2631

East Asian (EAS) AF: 0.000578 AC: 2 AN: 3461

South Asian (SAS) AF: 0.0225 AC: 58 AN: 2575

European-Finnish (FIN) AF: 0.0500 AC: 293 AN: 5855

Middle Eastern (MID) AF: 0.0943 AC: 20 AN: 212

European-Non Finnish (NFE) AF: 0.0800 AC: 4227 AN: 52857

Other (OTH) AF: 0.0974 AC: 146 AN: 1499

Alfa AF: 0.0817 Hom.: 3521

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
PhyloP100		0.21
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: rs12011518; hg19: chrX-66933036;