rs146283342

Variant names:

• chrX-67711342-G-A
• rs146283342
• NM_000044.6:c.1886-60G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-67711342-G-A
• chrX-67711342-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000044.6(AR):​c.1886-60G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,134,240 control chromosomes in the GnomAD database, including 48 homozygotes. There are 631 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., 316 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (28 hom. 315 hem.)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.246

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=-0.89).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1198/112114) while in subpopulation AFR AF= 0.0372 (1146/30835). AF 95% confidence interval is 0.0354. There are 20 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1886-60G>A		intron_variant	Intron 3 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.290-60G>A		intron_variant	Intron 4 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1886-60G>A		intron_variant	Intron 3 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.1886-60G>A		intron_variant	Intron 3 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*234-60G>A		intron_variant	Intron 4 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.1886-60G>A		intron_variant	Intron 3 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1194 AN: 112061 Hom.: 20 Cov.: 23 AF XY: 0.00915 AC XY: 313 AN XY: 34219

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00732

GnomAD4 exome AF: 0.00119 AC: 1221 AN: 1022126 Hom.: 28 AF XY: 0.000990 AC XY: 315 AN XY: 318316

Gnomad4 AFR exome AF: 0.0409

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000615

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000696

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.0107 AC: 1198 AN: 112114 Hom.: 20 Cov.: 23 AF XY: 0.00922 AC XY: 316 AN XY: 34282

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00312

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00723

Alfa AF: 0.00420 Hom.: 4

Bravo AF: 0.0121

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Androgen resistance syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.44

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: rs146283342; hg19: chrX-66931184;