X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1382_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000044.6(AR):​c.1382_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly461_Gly473del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 559,165 control chromosomes in the GnomAD database, including 430 homozygotes. There are 1,904 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., 94 hem., cov: 0)
  • Exomes 𝑓: 0.013 (429 hom. 1810 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter 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 Benign. Variant got -10 ACMG points.

• BP6: Variant X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1299195.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00454 (377/83056) while in subpopulation NFE AF= 0.00686 (296/43135). AF 95% confidence interval is 0.00622. There are 1 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 94 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1382_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly461_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1382_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly461_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 377 AN: 83052 Hom.: 1 Cov.: 0 AF XY: 0.00566 AC XY: 94 AN XY: 16616

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00410

Gnomad ASJ AF: 0.00180

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00686

Gnomad OTH AF: 0.00472

GnomAD3 exomes AF: 0.0113 AC: 426 AN: 37570 Hom.: 75 AF XY: 0.0112 AC XY: 146 AN XY: 12980

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.00122

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.00581

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0130 AC: 6173 AN: 476109 Hom.: 429 AF XY: 0.0153 AC XY: 1810 AN XY: 118153

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00804

Gnomad4 ASJ exome AF: 0.00576

Gnomad4 EAS exome AF: 0.000213

Gnomad4 SAS exome AF: 0.00340

Gnomad4 FIN exome AF: 0.00631

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00454 AC: 377 AN: 83056 Hom.: 1 Cov.: 0 AF XY: 0.00565 AC XY: 94 AN XY: 16626

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00410

Gnomad4 ASJ AF: 0.00180

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00131

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00686

Gnomad4 OTH AF: 0.00465

Bravo AF: 0.00411

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;