X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000044.6(AR):​c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly464_Gly473del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 559,079 control chromosomes in the GnomAD database, including 77 homozygotes. There are 244 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., 21 hem., cov: 0)
  • Exomes 𝑓: 0.0016 (77 hom. 223 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.29

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0016 (764/476023) while in subpopulation MID AF= 0.0138 (18/1306). AF 95% confidence interval is 0.00891. There are 77 homozygotes in gnomad4_exome. There are 223 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.000963 AC: 80 AN: 83052 Hom.: 0 Cov.: 0 AF XY: 0.00126 AC XY: 21 AN XY: 16618

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.000450

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00513

Gnomad NFE AF: 0.000811

Gnomad OTH AF: 0.00283

GnomAD4 exome AF: 0.00160 AC: 764 AN: 476023 Hom.: 77 AF XY: 0.00189 AC XY: 223 AN XY: 118101

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.000314

Gnomad4 EAS exome AF: 0.00213

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.0000915

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.000963 AC: 80 AN: 83056 Hom.: 0 Cov.: 0 AF XY: 0.00126 AC XY: 21 AN XY: 16628

Gnomad4 AFR AF: 0.00134

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.000450

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000811

Gnomad4 OTH AF: 0.00279

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AR-related disorder Benign:1

Dec 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356;