X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGC

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000044.6(AR):​c.1406_1420del​(p.Gly469_Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 552,271 control chromosomes in the GnomAD database, including 427 homozygotes. There are 995 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G457G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., 156 hem., cov: 0)
  • Exomes 𝑓: 0.0078 (420 hom. 839 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-67546514-TGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 434259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1406_1420del	p.Gly469_Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1406_1420del	p.Gly469_Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 750 AN: 83037 Hom.: 7 Cov.: 0 AF XY: 0.00939 AC XY: 156 AN XY: 16605

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00270

Gnomad EAS AF: 0.00971

Gnomad SAS AF: 0.00328

Gnomad FIN AF: 0.00168

Gnomad MID AF: 0.0205

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.0189

GnomAD3 exomes AF: 0.0106 AC: 397 AN: 37570 Hom.: 115 AF XY: 0.00539 AC XY: 70 AN XY: 12980

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.00128

Gnomad EAS exome AF: 0.0451

Gnomad SAS exome AF: 0.00495

Gnomad FIN exome AF: 0.00224

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.00784 AC: 3678 AN: 469230 Hom.: 420 AF XY: 0.00725 AC XY: 839 AN XY: 115712

Gnomad4 AFR exome AF: 0.0422

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.0544

Gnomad4 SAS exome AF: 0.00650

Gnomad4 FIN exome AF: 0.00295

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00940

GnomAD4 genome AF: 0.00904 AC: 751 AN: 83041 Hom.: 7 Cov.: 0 AF XY: 0.00939 AC XY: 156 AN XY: 16615

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00270

Gnomad4 EAS AF: 0.00975

Gnomad4 SAS AF: 0.00329

Gnomad4 FIN AF: 0.00168

Gnomad4 NFE AF: 0.00267

Gnomad4 OTH AF: 0.0186

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2016

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2021

- -

AR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2019

This variant is classified as 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;