X-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Position:

• chrX-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

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

The NM_000044.6(AR):​c.231_239delGCAGCAGCA​(p.Gln78_Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 982,901 control chromosomes in the GnomAD database, including 418 homozygotes. There are 3,243 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (308 hom., 647 hem., cov: 0)
  • Exomes 𝑓: 0.024 (110 hom. 2596 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.40

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-67545316-TGCAGCAGCA-T is Benign according to our data. Variant chrX-67545316-TGCAGCAGCA-T is described in ClinVar as [Likely_benign]. Clinvar id is 210223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67545316-TGCAGCAGCA-T is described in Lovd as [Benign]. Variant chrX-67545316-TGCAGCAGCA-T is described in Lovd as [Benign]. Variant chrX-67545316-TGCAGCAGCA-T is described in Lovd as [Likely_benign]. Variant chrX-67545316-TGCAGCAGCA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	1/8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	1/8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 6492 AN: 66530 Hom.: 308 Cov.: 0 AF XY: 0.0786 AC XY: 645 AN XY: 8202

Gnomad AFR AF: 0.0956

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0921

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.0670

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0961

GnomAD4 exome AF: 0.0237 AC: 21760 AN: 916384 Hom.: 110 AF XY: 0.00938 AC XY: 2596 AN XY: 276646

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.0250

Gnomad4 ASJ exome AF: 0.0473

Gnomad4 EAS exome AF: 0.0320

Gnomad4 SAS exome AF: 0.0176

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0976 AC: 6493 AN: 66517 Hom.: 308 Cov.: 0 AF XY: 0.0788 AC XY: 647 AN XY: 8215

Gnomad4 AFR AF: 0.0957

Gnomad4 AMR AF: 0.0731

Gnomad4 ASJ AF: 0.0921

Gnomad4 EAS AF: 0.0391

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.0659

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0949

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 30, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2022

- -

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: rs3032358; hg19: chrX-66765158;