NM_000044.6:c.216_239dupGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_000044.6(AR):c.216_239dupGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln73_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 0.0035 ( 7 hom., 13 hem., cov: 0)

Exomes 𝑓: 0.0013 ( 0 hom. 75 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: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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000044.6

BP6

Variant X-67545316-T-TGCAGCAGCAGCAGCAGCAGCAGCA is Benign according to our data. Variant chrX-67545316-T-TGCAGCAGCAGCAGCAGCAGCAGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 464794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.216_239dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln73_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.216_239dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln73_Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

231

AN:

66631

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00459

Gnomad ASJ

AF:

0.0227

Gnomad EAS

AF:

0.00432

Gnomad SAS

AF:

0.00548

Gnomad FIN

AF:

0.00346

Gnomad MID

AF:

0.00654

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00249

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00132

AC:

1232

AN:

936378

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

294596

show subpopulations

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

African (AFR)

AF:

0.000631

AC:

AN:

23753

American (AMR)

AF:

0.00201

AC:

AN:

25823

Ashkenazi Jewish (ASJ)

AF:

0.00884

AC:

143

AN:

16184

East Asian (EAS)

AF:

0.00396

AC:

112

AN:

28294

South Asian (SAS)

AF:

0.00164

AC:

AN:

45095

European-Finnish (FIN)

AF:

0.00279

AC:

101

AN:

36149

Middle Eastern (MID)

AF:

0.00116

AC:

AN:

2594

European-Non Finnish (NFE)

AF:

0.000896

AC:

644

AN:

718635

Other (OTH)

AF:

0.00221

AC:

AN:

39851

⚠️ 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: 0.352

Heterozygous variant carriers

122

184

245

306

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:

0.00345

AC:

230

AN:

66618

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

AN XY:

8258

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

18797

American (AMR)

AF:

0.00458

AC:

AN:

5236

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

AN:

1715

East Asian (EAS)

AF:

0.00434

AC:

AN:

1843

South Asian (SAS)

AF:

0.00555

AC:

AN:

901

European-Finnish (FIN)

AF:

0.00346

AC:

AN:

2025

Middle Eastern (MID)

AF:

0.00

AC:

AN:

133

European-Non Finnish (NFE)

AF:

0.00337

AC:

117

AN:

34710

Other (OTH)

AF:

0.00246

AC:

AN:

812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

237

Bravo

AF:

0.0000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 31, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Jan 20, 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

(source)

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