14-92071009-C-CG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004993.6(ATXN3):c.916_917insC(p.Gly306AlafsTer12) variant causes a frameshift 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. G306G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.48 ( 3821 hom., cov: 22)

Exomes 𝑓: 0.36 ( 39001 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: -0.802

Publications

6 publications found

Variant links:

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ATXN3 Gene-Disease associations (from GenCC):

Machado-Joseph disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Machado-Joseph disease type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Machado-Joseph disease type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Machado-Joseph disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATXN3 links:

ENSG00000303901 (HGNC:):

ENSG00000303901 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 14-92071009-C-CG is Benign according to our data. Variant chr14-92071009-C-CG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402402.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.916_917insC	p.Gly306AlafsTer12	frameshift_variant	Exon 10 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2 link	c.916_917insC	p.Gly306AlafsTer12	frameshift_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

31454

AN:

65716

Hom.:

3825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.475

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.539

Gnomad FIN

AF:

0.453

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.479

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.360

AC:

279659

AN:

776368

Hom.:

39001

Cov.:

AF XY:

0.361

AC XY:

141447

AN XY:

392262

show subpopulations

African (AFR)

AF:

0.234

AC:

2777

AN:

11892

American (AMR)

AF:

0.236

AC:

4550

AN:

19312

Ashkenazi Jewish (ASJ)

AF:

0.426

AC:

6561

AN:

15406

East Asian (EAS)

AF:

0.427

AC:

14522

AN:

34014

South Asian (SAS)

AF:

0.380

AC:

19068

AN:

50242

European-Finnish (FIN)

AF:

0.329

AC:

10508

AN:

31950

Middle Eastern (MID)

AF:

0.397

AC:

1134

AN:

2858

European-Non Finnish (NFE)

AF:

0.361

AC:

209095

AN:

578514

Other (OTH)

AF:

0.356

AC:

11444

AN:

32180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

11150

22300

33450

44600

55750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6422

12844

19266

25688

32110

<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

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.479

AC:

31448

AN:

65706

Hom.:

3821

Cov.:

AF XY:

0.477

AC XY:

15334

AN XY:

32146

show subpopulations

African (AFR)

AF:

0.475

AC:

5441

AN:

11444

American (AMR)

AF:

0.437

AC:

2390

AN:

5468

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1082

AN:

2026

East Asian (EAS)

AF:

0.462

AC:

2020

AN:

4372

South Asian (SAS)

AF:

0.540

AC:

1440

AN:

2668

European-Finnish (FIN)

AF:

0.453

AC:

2401

AN:

5296

Middle Eastern (MID)

AF:

0.494

AC:

AN:

156

European-Non Finnish (NFE)

AF:

0.484

AC:

15938

AN:

32928

Other (OTH)

AF:

0.480

AC:

436

AN:

908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1051

2102

3154

4205

5256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.119

Hom.:

383

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Repeat expansion in gene is associated with Machado-Joseph disease.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Azorean disease

Uncertain:1

Jan 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ATXN3-related disorder

Benign:1

Nov 04, 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

-0.80

Mutation Taster

=154/46

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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