X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1409_1420delGCGGCGGCGGCG

Variant summary

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

The NM_000044.6(AR):​c.1409_1420delGCGGCGGCGGCG​(p.Gly470_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 0.074 in 555,074 control chromosomes in the GnomAD database, including 3,978 homozygotes. There are 10,692 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (80 hom., 688 hem., cov: 0)
  • Exomes 𝑓: 0.080 (3898 hom. 10004 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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-TGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 464784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1409_1420delGCGGCGGCGGCG	p.Gly470_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.1409_1420delGCGGCGGCGGCG	p.Gly470_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 3405 AN: 83005 Hom.: 80 Cov.: 0 AF XY: 0.0416 AC XY: 689 AN XY: 16573

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0292

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0284

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0359

Gnomad NFE AF: 0.0523

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0598 AC: 2248 AN: 37570 Hom.: 474 AF XY: 0.0514 AC XY: 667 AN XY: 12980

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.0482

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0994

Gnomad NFE exome AF: 0.0534

Gnomad OTH exome AF: 0.0588

GnomAD4 exome AF: 0.0798 AC: 37682 AN: 472065 Hom.: 3898 AF XY: 0.0868 AC XY: 10004 AN XY: 115189

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.0660

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.0805

Gnomad4 OTH exome AF: 0.0751

GnomAD4 genome AF: 0.0410 AC: 3403 AN: 83009 Hom.: 80 Cov.: 0 AF XY: 0.0415 AC XY: 688 AN XY: 16583

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0284

Gnomad4 EAS AF: 0.0403

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.0523

Gnomad4 OTH AF: 0.0400

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 19, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Androgen resistance syndrome Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;