NM_000044.6:c.1412_1420dupGCGGCGGCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000044.6(AR):c.1412_1420dupGCGGCGGCG(p.Gly471_Gly473dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 12 hom., 94 hem., cov: 0)

Exomes 𝑓: 0.0055 ( 22 hom. 583 hem. )

Failed GnomAD Quality Control

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

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 -9 ACMG points.

BP6

Variant X-67546514-T-TGGCGGCGGC is Benign according to our data. Variant chrX-67546514-T-TGGCGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 638387.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00937 (778/83055) while in subpopulation AFR AF = 0.0171 (370/21649). AF 95% confidence interval is 0.0157. There are 12 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1412_1420dupGCGGCGGCG	p.Gly471_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.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00937

AC:

778

AN:

83051

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0171

Gnomad AMI

AF:

0.0409

Gnomad AMR

AF:

0.00922

Gnomad ASJ

AF:

0.00225

Gnomad EAS

AF:

0.00505

Gnomad SAS

AF:

0.0144

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.00542

Gnomad OTH

AF:

0.0104

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00550

AC:

2614

AN:

475547

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

583

AN XY:

117847

show subpopulations

African (AFR)

AF:

0.00999

AC:

132

AN:

13211

American (AMR)

AF:

0.000233

AC:

AN:

8585

Ashkenazi Jewish (ASJ)

AF:

0.000838

AC:

AN:

9549

East Asian (EAS)

AF:

0.000709

AC:

AN:

14099

South Asian (SAS)

AF:

0.00544

AC:

AN:

14709

European-Finnish (FIN)

AF:

0.000457

AC:

AN:

21872

Middle Eastern (MID)

AF:

0.00536

AC:

AN:

1306

European-Non Finnish (NFE)

AF:

0.00605

AC:

2249

AN:

371630

Other (OTH)

AF:

0.00563

AC:

116

AN:

20586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00937

AC:

778

AN:

83055

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

AN XY:

16629

show subpopulations

African (AFR)

AF:

0.0171

AC:

370

AN:

21649

American (AMR)

AF:

0.00921

AC:

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.00225

AC:

AN:

2222

East Asian (EAS)

AF:

0.00507

AC:

AN:

2564

South Asian (SAS)

AF:

0.0145

AC:

AN:

1522

European-Finnish (FIN)

AF:

0.0118

AC:

AN:

2381

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.00542

AC:

234

AN:

43137

Other (OTH)

AF:

0.0102

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

126

158

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.:

327

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Androgen resistance syndrome

Uncertain:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AR-related disorder

Benign:1

Jan 24, 2023

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

1.3

Mutation Taster

=78/22

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