X-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCA

Position:

• chrX-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000044.6(AR):​c.204_239del​(p.Gln69_Gln80del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,003,942 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., 10 hem., cov: 0)
  • Exomes 𝑓: 0.00011 (0 hom. 29 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant X-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-T is Benign according to our data. Variant chrX-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-T is described in ClinVar as [Benign]. Clinvar id is 1556388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.204_239del	p.Gln69_Gln80del	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.204_239del	p.Gln69_Gln80del	inframe_deletion	1/8	1	NM_000044.6	ENSP00000363822	P1

Frequencies

GnomAD3 genomes AF: 0.000840 AC: 56 AN: 66636 Hom.: 0 Cov.: 0 AF XY: 0.00121 AC XY: 10 AN XY: 8246

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000765

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000317

Gnomad OTH AF: 0.00125

GnomAD4 exome AF: 0.000106 AC: 99 AN: 937306 Hom.: 0 AF XY: 0.0000982 AC XY: 29 AN XY: 295396

Gnomad4 AFR exome AF: 0.000295

Gnomad4 AMR exome AF: 0.0000387

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000705

Gnomad4 SAS exome AF: 0.000155

Gnomad4 FIN exome AF: 0.0000829

Gnomad4 NFE exome AF: 0.0000946

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.000840 AC: 56 AN: 66636 Hom.: 0 Cov.: 0 AF XY: 0.00121 AC XY: 10 AN XY: 8246

Gnomad4 AFR AF: 0.00208

Gnomad4 AMR AF: 0.000765

Gnomad4 ASJ AF: 0.000583

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000317

Gnomad4 OTH AF: 0.00125

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

AR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2023

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: rs3032358; hg19: chrX-66765158;