NM_000044.6:c.225_239dupGCAGCAGCAGCAGCA

Variant names:

• chrX-67545316-T-TGCAGCAGCAGCAGCA
• rs3032358
• NM_000044.6:c.225_239dupGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_000044.6(AR):​c.225_239dupGCAGCAGCAGCAGCA​(p.Gln76_Gln80dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q80Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., 74 hem., cov: 0)
  • Exomes 𝑓: 0.0067 (10 hom. 419 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.337
• Publications: 10 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BP6: Variant X-67545316-T-TGCAGCAGCAGCAGCA is Benign according to our data. Variant chrX-67545316-T-TGCAGCAGCAGCAGCA is described in ClinVar as Benign. ClinVar VariationId is 464795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0196 (1304/66608) while in subpopulation EAS AF = 0.0402 (74/1841). AF 95% confidence interval is 0.0328. There are 36 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.225_239dupGCAGCAGCAGCAGCA	p.Gln76_Gln80dup	disruptive_inframe_insertion	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.225_239dupGCAGCAGCAGCAGCA	p.Gln76_Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 1304 AN: 66621 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0112

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0327

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0150

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00673 AC: 6273 AN: 932512 Hom.: 10 Cov.: 40 AF XY: 0.00144 AC XY: 419 AN XY: 290870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00380 AC: 90 AN: 23707

American (AMR) AF: 0.0141 AC: 360 AN: 25614

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 213 AN: 16121

East Asian (EAS) AF: 0.0262 AC: 732 AN: 27913

South Asian (SAS) AF: 0.00757 AC: 337 AN: 44516

European-Finnish (FIN) AF: 0.0180 AC: 645 AN: 35852

Middle Eastern (MID) AF: 0.00931 AC: 24 AN: 2578

European-Non Finnish (NFE) AF: 0.00491 AC: 3517 AN: 716556

Other (OTH) AF: 0.00895 AC: 355 AN: 39655

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0196 AC: 1304 AN: 66608 Hom.: 36 Cov.: 0 AF XY: 0.00896 AC XY: 74 AN XY: 8256

African (AFR) AF: 0.0118 AC: 222 AN: 18799

American (AMR) AF: 0.0250 AC: 131 AN: 5236

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 47 AN: 1714

East Asian (EAS) AF: 0.0402 AC: 74 AN: 1841

South Asian (SAS) AF: 0.0266 AC: 24 AN: 901

European-Finnish (FIN) AF: 0.0222 AC: 45 AN: 2025

Middle Eastern (MID) AF: 0.0376 AC: 5 AN: 133

European-Non Finnish (NFE) AF: 0.0213 AC: 739 AN: 34701

Other (OTH) AF: 0.0148 AC: 12 AN: 812

Alfa AF: 0.00 Hom.: 237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AR c.225_239dup15 (p.Gln76_Gln80dup) results in an in-frame duplication that is predicted to duplicate five amino acids into the encoded protein. Diagnosis of Spinal and bulbar muscular atrophy is established based on the identification of an expansion of CAG trinucleotide repeat of >35 CAGs whereas the current variant involves 28 CAGs. Additionally, this in-frame duplication is not consistent with the molecular mechanism of disease for Androgen Resistance Syndrome. The variant was absent in 166414 control chromosomes, however this region of the gene in gnomad contains numerous high frequency duplications/deletions, with dubious quality annotation due to low complexity region. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.225_239dup15 has been reported in the literature in an individual affected with Hypospadias (Xie_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35729303). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AR p.Gln76_Gln80dup variant was not identified in the literature nor was it identified in the dbSNP, COGR, Cosmic, MutDB, and UMD-LSDB databases. The variant was also identified in ClinVar as benign with one submission from Invitae with the associated conditions of Androgen resistance syndrome and Bulbo-spinal atrophy X-linked. The variant was also identified in LOVD 3.0. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion resulting in the duplication of a glutamine (gln) residue at codon 76; the impact of this alteration on AR protein function is not known, however this insertion occurs in a variable poly-Q repeat region and was predicted to be a polymorphism by MutationTaster. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Jul 06, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=69/31	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3032358; hg19: chrX-66765158; COSMIC: COSV65959057;