chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000044.6(AR):​c.1388_1420del​(p.Gly463_Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000588 in 559,143 control chromosomes in the GnomAD database, including 37 homozygotes. There are 92 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G457G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., 14 hem., cov: 0)
  • Exomes 𝑓: 0.00056 (36 hom. 78 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1388_1420del	p.Gly463_Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1388_1420del	p.Gly463_Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.000746 AC: 62 AN: 83056 Hom.: 1 Cov.: 0 AF XY: 0.000782 AC XY: 13 AN XY: 16620

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.000900

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000278

Gnomad OTH AF: 0.000943

GnomAD4 exome AF: 0.000559 AC: 266 AN: 476083 Hom.: 36 AF XY: 0.000660 AC XY: 78 AN XY: 118139

Gnomad4 AFR exome AF: 0.00250

Gnomad4 AMR exome AF: 0.00303

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.000355

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.0000915

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.000758 AC: 63 AN: 83060 Hom.: 1 Cov.: 0 AF XY: 0.000842 AC XY: 14 AN XY: 16630

Gnomad4 AFR AF: 0.00134

Gnomad4 AMR AF: 0.00217

Gnomad4 ASJ AF: 0.000900

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00131

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000278

Gnomad4 OTH AF: 0.000929

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2021

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with AR-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant, c.1388_1420del, results in the deletion of 11 amino acid(s) of the AR protein (p.Gly463_Gly473del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

AR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2021

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;