NM_000044.6:c.207_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_000044.6(AR):c.207_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln70_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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q80Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., 4 hem., cov: 0)

Exomes 𝑓: 0.00018 ( 0 hom. 17 hem. )

Failed GnomAD Quality Control

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

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: Benign. The variant received -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000044.6

BP6

Variant X-67545316-T-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA is Benign according to our data. Variant chrX-67545316-T-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA is described in ClinVar as Likely_benign. ClinVar VariationId is 1200448.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.207_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln70_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.207_239dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln70_Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

66634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000765

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.000540

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000490

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000179

AC:

168

AN:

937189

Hom.:

Cov.:

AF XY:

0.0000576

AC XY:

AN XY:

295285

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:

23759

American (AMR)

AF:

0.000580

AC:

AN:

25855

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16269

East Asian (EAS)

AF:

0.000811

AC:

AN:

28361

South Asian (SAS)

AF:

0.000221

AC:

AN:

45222

European-Finnish (FIN)

AF:

0.0000553

AC:

AN:

36190

Middle Eastern (MID)

AF:

0.000385

AC:

AN:

2596

European-Non Finnish (NFE)

AF:

0.000152

AC:

109

AN:

719041

Other (OTH)

AF:

0.000150

AC:

AN:

39896

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.000420

AC:

AN:

66621

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

8259

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

18797

American (AMR)

AF:

0.000764

AC:

AN:

5236

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

1715

East Asian (EAS)

AF:

0.000543

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:

0.000490

AC:

AN:

34713

Other (OTH)

AF:

0.00

AC:

AN:

812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.627

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: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AR-related disorder

Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

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