X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGC

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGC

Variant summary

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

The NM_000044.6(AR):​c.1397_1420del​(p.Gly466_Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 559,009 control chromosomes in the GnomAD database, including 125 homozygotes. There are 397 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G457G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., 44 hem., cov: 0)
  • Exomes 𝑓: 0.0026 (123 hom. 353 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -6 ACMG points.

• BP6: Variant X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1167648.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign]. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1397_1420del	p.Gly466_Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1397_1420del	p.Gly466_Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 243 AN: 83052 Hom.: 2 Cov.: 0 AF XY: 0.00259 AC XY: 43 AN XY: 16616

Gnomad AFR AF: 0.00693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00495

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00513

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00377

GnomAD3 exomes AF: 0.00532 AC: 200 AN: 37570 Hom.: 64 AF XY: 0.00339 AC XY: 44 AN XY: 12980

Gnomad AFR exome AF: 0.0871

Gnomad AMR exome AF: 0.00935

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.0341

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00263 AC: 1253 AN: 475953 Hom.: 123 AF XY: 0.00299 AC XY: 353 AN XY: 118113

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.00502

Gnomad4 ASJ exome AF: 0.00649

Gnomad4 EAS exome AF: 0.00298

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00293 AC: 243 AN: 83056 Hom.: 2 Cov.: 0 AF XY: 0.00265 AC XY: 44 AN XY: 16626

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.00243

Gnomad4 ASJ AF: 0.00495

Gnomad4 EAS AF: 0.000780

Gnomad4 SAS AF: 0.00131

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00372

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 24, 2024

- -

AR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 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;