X-67546514-TGGC-T

Position:

• chrX-67546514-TGGC-T

Variant summary

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

The NM_000044.6(AR):​c.1418_1420del​(p.Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 461,058 control chromosomes in the GnomAD database, including 353 homozygotes. There are 1,662 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G457G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.061 (382 hom., 692 hem., cov: 0)
  • Exomes 𝑓: 0.022 (353 hom. 1662 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-67546514-TGGC-T is Benign according to our data. Variant chrX-67546514-TGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 464785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGC-T is described in Lovd as [Likely_benign]. Variant chrX-67546514-TGGC-T is described in Lovd as [Likely_benign]. Variant chrX-67546514-TGGC-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1418_1420del	p.Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1418_1420del	p.Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.0612 AC: 5078 AN: 83002 Hom.: 381 Cov.: 0 AF XY: 0.0419 AC XY: 696 AN XY: 16614

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.00495

Gnomad EAS AF: 0.0528

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0500

GnomAD4 exome AF: 0.0218 AC: 10065 AN: 461058 Hom.: 353 AF XY: 0.0150 AC XY: 1662 AN XY: 110626

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00491

Gnomad4 EAS exome AF: 0.0343

Gnomad4 SAS exome AF: 0.00848

Gnomad4 FIN exome AF: 0.0410

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0242

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0612 AC: 5078 AN: 83006 Hom.: 382 Cov.: 0 AF XY: 0.0416 AC XY: 692 AN XY: 16624

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.00495

Gnomad4 EAS AF: 0.0531

Gnomad4 SAS AF: 0.00329

Gnomad4 FIN AF: 0.0273

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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;