X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000044.6(AR):c.1415_1420dupGCGGCG(p.Gly472_Gly473dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 54 hom., 325 hem., cov: 0)

Exomes 𝑓: 0.017 ( 147 hom. 1890 hem. )

Failed GnomAD Quality Control

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.29

Publications

6 publications found

Variant links:

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

AR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant X-67546514-T-TGGCGGC is Benign according to our data. Variant chrX-67546514-T-TGGCGGC is described in ClinVar as [Likely_benign]. Clinvar id is 434265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0285 (2363/83023) while in subpopulation AFR AF = 0.0457 (989/21636). AF 95% confidence interval is 0.0433. There are 54 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1415_1420dupGCGGCG	p.Gly472_Gly473dup	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 link	c.1415_1420dupGCGGCG	p.Gly472_Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.0284

AC:

2360

AN:

83019

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.0257

Gnomad EAS

AF:

0.0163

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0513

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0340

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0170

AC:

8096

AN:

475254

Hom.:

147

Cov.:

AF XY:

0.0161

AC XY:

1890

AN XY:

117724

show subpopulations

African (AFR)

AF:

0.0267

AC:

352

AN:

13185

American (AMR)

AF:

0.00163

AC:

AN:

8578

Ashkenazi Jewish (ASJ)

AF:

0.00555

AC:

AN:

9542

East Asian (EAS)

AF:

0.00156

AC:

AN:

14096

South Asian (SAS)

AF:

0.0137

AC:

202

AN:

14701

European-Finnish (FIN)

AF:

0.000595

AC:

AN:

21867

Middle Eastern (MID)

AF:

0.0200

AC:

AN:

1303

European-Non Finnish (NFE)

AF:

0.0192

AC:

7129

AN:

371409

Other (OTH)

AF:

0.0139

AC:

285

AN:

20573

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

255

509

764

1018

1273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0285

AC:

2363

AN:

83023

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

325

AN XY:

16619

show subpopulations

African (AFR)

AF:

0.0457

AC:

989

AN:

21636

American (AMR)

AF:

0.0233

AC:

182

AN:

7808

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

AN:

2222

East Asian (EAS)

AF:

0.0164

AC:

AN:

2564

South Asian (SAS)

AF:

0.0243

AC:

AN:

1522

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

2382

Middle Eastern (MID)

AF:

0.0575

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.0232

AC:

999

AN:

43126

Other (OTH)

AF:

0.0335

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00337

Hom.:

327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2024

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.1415_1420dupGCGGCG (p.Gly472_Gly473dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.019 in 558277 control chromosomes in the gnomAD database, including 201 homozygotes. The observed variant frequency is above the estimated maximal expected allele frequency for a pathogenic variant in AR causing Androgen Resistance Syndrome strongly suggesting that the variant is benign. c.1415_1420dupGCGGCG has been reported in the literature in an individual affected with Androgen Resistance Syndrome (Wu_2018). 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: 29693241). ClinVar contains an entry for this variant (Variation ID: 434265). Based on the evidence outlined above, the variant was classified as benign. -

Oct 04, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome;C0376358:Prostate cancer;C1839259:Kennedy disease;C2678098:Hypospadias 1, X-linked

Benign:1

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AR: BS1, BS2 -

AR-related disorder

Benign:1

Apr 19, 2023

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

=78/22

polymorphism (auto)

(source)

Splicing

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

Publications

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X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over