X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGC

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000044.6(AR):​c.1400_1420del​(p.Gly467_Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 558,215 control chromosomes in the GnomAD database, including 548 homozygotes. There are 2,000 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 0.0062 (3 hom., 118 hem., cov: 0)
  • Exomes 𝑓: 0.014 (545 hom. 1882 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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-TGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1166508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.014 (6641/475159) while in subpopulation AMR AF= 0.0166 (142/8537). AF 95% confidence interval is 0.0156. There are 545 homozygotes in gnomad4_exome. There are 1882 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1400_1420del	p.Gly467_Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1400_1420del	p.Gly467_Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 506 AN: 83052 Hom.: 2 Cov.: 0 AF XY: 0.00704 AC XY: 117 AN XY: 16616

Gnomad AFR AF: 0.00684

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00769

Gnomad ASJ AF: 0.000450

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00196

Gnomad FIN AF: 0.00210

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00656

Gnomad OTH AF: 0.00189

GnomAD3 exomes AF: 0.0121 AC: 455 AN: 37570 Hom.: 139 AF XY: 0.00840 AC XY: 109 AN XY: 12980

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.000319

Gnomad EAS exome AF: 0.0171

Gnomad SAS exome AF: 0.00478

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0140 AC: 6641 AN: 475159 Hom.: 545 AF XY: 0.0160 AC XY: 1882 AN XY: 117809

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.000210

Gnomad4 EAS exome AF: 0.00206

Gnomad4 SAS exome AF: 0.00999

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.00987

GnomAD4 genome AF: 0.00615 AC: 511 AN: 83056 Hom.: 3 Cov.: 0 AF XY: 0.00710 AC XY: 118 AN XY: 16626

Gnomad4 AFR AF: 0.00684

Gnomad4 AMR AF: 0.00832

Gnomad4 ASJ AF: 0.000450

Gnomad4 EAS AF: 0.00156

Gnomad4 SAS AF: 0.00197

Gnomad4 FIN AF: 0.00210

Gnomad4 NFE AF: 0.00656

Gnomad4 OTH AF: 0.00186

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 09, 2018

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

AR: BS1, BS2 -

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;