X-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000044.6(AR):c.201_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln68_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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q80Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 1 hem., cov: 0)

Exomes 𝑓: 0.000069 ( 0 hom. 10 hem. )

Failed GnomAD Quality Control

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 0.337

Publications

10 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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000044.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.201_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln68_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 link	c.201_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln68_Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.000240

AC:

AN:

66636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00162

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000288

Gnomad OTH

AF:

0.00125

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000694

AC:

AN:

937273

Hom.:

Cov.:

AF XY:

0.0000339

AC XY:

AN XY:

295385

show subpopulations

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

African (AFR)

AF:

0.0000842

AC:

AN:

23762

American (AMR)

AF:

0.000271

AC:

AN:

25859

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16269

East Asian (EAS)

AF:

0.000176

AC:

AN:

28381

South Asian (SAS)

AF:

0.0000663

AC:

AN:

45240

European-Finnish (FIN)

AF:

0.0000276

AC:

AN:

36185

Middle Eastern (MID)

AF:

0.000385

AC:

AN:

2596

European-Non Finnish (NFE)

AF:

0.0000556

AC:

AN:

719085

Other (OTH)

AF:

0.000150

AC:

AN:

39896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000502931), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.380

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000240

AC:

AN:

66623

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

8259

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

18799

American (AMR)

AF:

0.00

AC:

AN:

5236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1715

East Asian (EAS)

AF:

0.00163

AC:

AN:

1843

South Asian (SAS)

AF:

0.00

AC:

AN:

901

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2025

Middle Eastern (MID)

AF:

0.00

AC:

AN:

133

European-Non Finnish (NFE)

AF:

0.000288

AC:

AN:

34713

Other (OTH)

AF:

0.00123

AC:

AN:

812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jul 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kennedy disease

Uncertain:1

Jan 26, 2017

GeneReviews

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

AR-related disorder

Uncertain:1

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AR c.201_239dup39 variant is predicted to result in an in-frame duplication (p.Gln68_Gln80dup). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.34

Splicing

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

Publications

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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