rs12396249

Positions:

• chrX-67557224-G-A
• chrX-67557224-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.1616+10462G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 110,501 control chromosomes in the GnomAD database, including 1,844 homozygotes. There are 5,603 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 0.19 (1844 hom., 5603 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.1616+10462G>A		intron_variant		ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1616+10462G>A		intron_variant		1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.190 AC: 20989 AN: 110447 Hom.: 1848 Cov.: 22 AF XY: 0.171 AC XY: 5593 AN XY: 32707

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.190 AC: 20994 AN: 110501 Hom.: 1844 Cov.: 22 AF XY: 0.171 AC XY: 5603 AN XY: 32771

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00114

Gnomad4 SAS AF: 0.0811

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.172

Alfa AF: 0.144 Hom.: 2698

Bravo AF: 0.195

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.49

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: rs12396249; hg19: chrX-66777066;