NM_000044.6:c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

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.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly462_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 0.00106 in 559,092 control chromosomes in the GnomAD database, including 55 homozygotes. There are 195 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. G462G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 5 hem., cov: 0)
  • Exomes 𝑓: 0.0012 (55 hom. 190 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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 sas. GnomAdExome4 allele frequency = 0.0012 (572/476032) while in subpopulation SAS AF = 0.00945 (139/14707). AF 95% confidence interval is 0.00817. There are 55 homozygotes in GnomAdExome4. There are 190 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 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_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.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 22 AN: 83056 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000384

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000209

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00120 AC: 572 AN: 476032 Hom.: 55 AF XY: 0.00161 AC XY: 190 AN XY: 118084

African (AFR) AF: 0.000151 AC: 2 AN: 13218

American (AMR) AF: 0.00303 AC: 26 AN: 8578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9545

East Asian (EAS) AF: 0.00241 AC: 34 AN: 14084

South Asian (SAS) AF: 0.00945 AC: 139 AN: 14707

European-Finnish (FIN) AF: 0.000183 AC: 4 AN: 21856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1303

European-Non Finnish (NFE) AF: 0.000938 AC: 349 AN: 372150

Other (OTH) AF: 0.000874 AC: 18 AN: 20591

GnomAD4 genome AF: 0.000265 AC: 22 AN: 83060 Hom.: 0 Cov.: 0 AF XY: 0.000301 AC XY: 5 AN XY: 16632

African (AFR) AF: 0.000185 AC: 4 AN: 21655

American (AMR) AF: 0.000384 AC: 3 AN: 7817

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2222

East Asian (EAS) AF: 0.00117 AC: 3 AN: 2564

South Asian (SAS) AF: 0.00197 AC: 3 AN: 1520

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.000209 AC: 9 AN: 43137

Other (OTH) AF: 0.00 AC: 0 AN: 1076

Alfa AF: 0.00 Hom.: 327

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypospadias 1, X-linked 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 Uncertain:1

Aug 23, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AR c.1385_1420del36 variant is predicted to result in an in-frame deletion (p.Gly462_Gly473del). This variant occurs within an exon 1 polyglycine track and leads to deletion of 12 glycine residues. This polyglycine track occurs downstream of the polyglutamine track where expansions are causative for spinal and bulbar muscular atrophy. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. However, there is some evidence in the literature suggesting that shorter polyglycine tracks may also be associated with AR-related disease (Werner et al. 2006. PubMed ID: 16804045; Hakimi et al. 1997. PubMed ID: 9815849). This variant has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/587547/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

- -

Androgen insensitivity, partial, with breast cancer 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

- -

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;