X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000044.6(AR):​c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly464_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 0.00151 in 559,079 control chromosomes in the GnomAD database, including 77 homozygotes. There are 244 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G464G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., 21 hem., cov: 0)
  • Exomes 𝑓: 0.0016 (77 hom. 223 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.29
• Publications: 6 publications found

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]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0016 (764/476023) while in subpopulation MID AF = 0.0138 (18/1306). AF 95% confidence interval is 0.00891. There are 77 homozygotes in GnomAdExome4. There are 223 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_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.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.000963 AC: 80 AN: 83052 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.000450

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00513

Gnomad NFE AF: 0.000811

Gnomad OTH AF: 0.00283

GnomAD4 exome AF: 0.00160 AC: 764 AN: 476023 Hom.: 77 AF XY: 0.00189 AC XY: 223 AN XY: 118101

African (AFR) AF: 0.00242 AC: 32 AN: 13217

American (AMR) AF: 0.00618 AC: 53 AN: 8578

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 3 AN: 9541

East Asian (EAS) AF: 0.00213 AC: 30 AN: 14079

South Asian (SAS) AF: 0.00190 AC: 28 AN: 14705

European-Finnish (FIN) AF: 0.0000915 AC: 2 AN: 21849

Middle Eastern (MID) AF: 0.0138 AC: 18 AN: 1306

European-Non Finnish (NFE) AF: 0.00147 AC: 547 AN: 372162

Other (OTH) AF: 0.00248 AC: 51 AN: 20586

GnomAD4 genome AF: 0.000963 AC: 80 AN: 83056 Hom.: 0 Cov.: 0 AF XY: 0.00126 AC XY: 21 AN XY: 16628

African (AFR) AF: 0.00134 AC: 29 AN: 21655

American (AMR) AF: 0.00102 AC: 8 AN: 7817

Ashkenazi Jewish (ASJ) AF: 0.000450 AC: 1 AN: 2222

East Asian (EAS) AF: 0.00117 AC: 3 AN: 2563

South Asian (SAS) AF: 0.00 AC: 0 AN: 1522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2382

Middle Eastern (MID) AF: 0.00575 AC: 1 AN: 174

European-Non Finnish (NFE) AF: 0.000811 AC: 35 AN: 43132

Other (OTH) AF: 0.00279 AC: 3 AN: 1076

Alfa AF: 0.00 Hom.: 327

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AR-related disorder Benign:1

Dec 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=199/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356; COSMIC: COSV101017518;