rs12014709

Variant names:

• chrX-67718624-T-G
• rs12014709
• NM_000044.6:c.2318+1002T>G

Variant summary

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

The NM_000044.6(AR):​c.2318+1002T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 110,436 control chromosomes in the GnomAD database, including 1,542 homozygotes. There are 4,242 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 0.15 (1542 hom., 4242 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.435
• Publications: 9 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2318+1002T>G		intron_variant	Intron 5 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.722+1002T>G		intron_variant	Intron 6 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2318+1002T>G		intron_variant	Intron 5 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2174-5062T>G		intron_variant	Intron 4 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*666+1002T>G		intron_variant	Intron 6 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.2318+1002T>G		intron_variant	Intron 5 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 16259 AN: 110387 Hom.: 1537 Cov.: 22

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.0189

Gnomad AMR AF: 0.0898

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.000572

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0507

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.148 AC: 16294 AN: 110436 Hom.: 1542 Cov.: 22 AF XY: 0.130 AC XY: 4242 AN XY: 32744

African (AFR) AF: 0.340 AC: 10253 AN: 30153

American (AMR) AF: 0.0897 AC: 937 AN: 10449

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 160 AN: 2633

East Asian (EAS) AF: 0.000573 AC: 2 AN: 3488

South Asian (SAS) AF: 0.0223 AC: 57 AN: 2554

European-Finnish (FIN) AF: 0.0507 AC: 300 AN: 5922

Middle Eastern (MID) AF: 0.128 AC: 27 AN: 211

European-Non Finnish (NFE) AF: 0.0816 AC: 4313 AN: 52825

Other (OTH) AF: 0.153 AC: 232 AN: 1513

Alfa AF: 0.0912 Hom.: 1636

Bravo AF: 0.161

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.36
PhyloP100		0.43
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: rs12014709; hg19: chrX-66938466;