rs12014709

Positions:

• chrX-67718624-T-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.82).
• 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/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2318+1002T>G		intron_variant		ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.722+1002T>G		intron_variant			NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2318+1002T>G		intron_variant		1	NM_000044.6	ENSP00000363822	P1
AR	ENST00000396044.8	c.2174-5062T>G		intron_variant		1		ENSP00000379359
AR	ENST00000396043.4	c.*666+1002T>G		intron_variant, NMD_transcript_variant		1		ENSP00000379358
AR	ENST00000612452.5	c.2318+1002T>G		intron_variant, NMD_transcript_variant		5		ENSP00000484033

Frequencies

GnomAD3 genomes AF: 0.147 AC: 16259 AN: 110387 Hom.: 1537 Cov.: 22 AF XY: 0.129 AC XY: 4218 AN XY: 32685

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

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.0897

Gnomad4 ASJ AF: 0.0608

Gnomad4 EAS AF: 0.000573

Gnomad4 SAS AF: 0.0223

Gnomad4 FIN AF: 0.0507

Gnomad4 NFE AF: 0.0816

Gnomad4 OTH AF: 0.153

Alfa AF: 0.0992 Hom.: 969

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

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: rs12014709; hg19: chrX-66938466;