14-92071010-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_004993.6(ATXN3):c.916G>C(p.Gly306Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 142,372 control chromosomes in the GnomAD database, including 4 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306delinsQQQQQQR) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 4 hom., cov: 22)

Exomes 𝑓: 0.040 ( 2689 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3O:1

Conservation

PhyloP100: -0.802

Publications

39 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002918005).

BP6

Variant 14-92071010-C-G is Benign according to our data. Variant chr14-92071010-C-G is described in ClinVar as [Benign]. Clinvar id is 128515.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.916G>C	p.Gly306Arg	missense_variant	Exon 10 of 11	ENST00000644486.2	NP_004984.2	P54252-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2 link	c.916G>C	p.Gly306Arg	missense_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1		P54252-2

Frequencies

GnomAD3 genomes

AF:

0.00569

AC:

809

AN:

142262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00313

Gnomad ASJ

AF:

0.00234

Gnomad EAS

AF:

0.0152

Gnomad SAS

AF:

0.00417

Gnomad FIN

AF:

0.00121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00245

Gnomad OTH

AF:

0.00671

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0396

AC:

52010

AN:

1313966

Hom.:

2689

Cov.:

AF XY:

0.0390

AC XY:

25632

AN XY:

656968

show subpopulations

African (AFR)

AF:

0.0524

AC:

1445

AN:

27562

American (AMR)

AF:

0.0305

AC:

1235

AN:

40506

Ashkenazi Jewish (ASJ)

AF:

0.0454

AC:

1108

AN:

24392

East Asian (EAS)

AF:

0.0541

AC:

2024

AN:

37418

South Asian (SAS)

AF:

0.0592

AC:

4699

AN:

79438

European-Finnish (FIN)

AF:

0.0201

AC:

981

AN:

48882

Middle Eastern (MID)

AF:

0.0393

AC:

202

AN:

5142

European-Non Finnish (NFE)

AF:

0.0382

AC:

38034

AN:

995550

Other (OTH)

AF:

0.0414

AC:

2282

AN:

55076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

1487

2974

4460

5947

7434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00568

AC:

809

AN:

142372

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

393

AN XY:

69160

show subpopulations

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

African (AFR)

AF:

0.0132

AC:

480

AN:

36240

American (AMR)

AF:

0.00312

AC:

AN:

14408

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

3412

East Asian (EAS)

AF:

0.0152

AC:

AN:

4610

South Asian (SAS)

AF:

0.00395

AC:

AN:

4308

European-Finnish (FIN)

AF:

0.00121

AC:

AN:

9878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00245

AC:

163

AN:

66396

Other (OTH)

AF:

0.00715

AC:

AN:

1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.384

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.106

Hom.:

161

Bravo

AF:

0.212

TwinsUK

AF:

0.235

AC:

872

ALSPAC

AF:

0.239

AC:

922

ESP6500AA

AF:

0.113

AC:

496

ESP6500EA

AF:

0.188

AC:

1619

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

ATXN3-related disorder

Benign:1

Oct 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). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Azorean disease

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.2

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.038

T;T;.;.;T;.;.;.;.;.;T;T;T;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.080

.;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

-0.80

PrimateAI

Benign

0.27

PROVEAN

Benign

0.28

.;.;N;.;.;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.048

Sift

Benign

0.15

.;.;T;.;.;T;T;T;D;T;T;T;T;T;.

Sift4G

Benign

0.66

.;T;T;T;T;T;T;T;T;.;.;.;.;.;T

Polyphen

0.0

B;.;.;.;B;.;.;B;.;.;.;.;.;.;.

Vest4

0.23, 0.23, 0.24, 0.23, 0.21, 0.25, 0.20, 0.27

MutPred

0.20

Gain of catalytic residue at L308 (P = 0.0509);.;.;.;Gain of catalytic residue at L308 (P = 0.0509);.;.;.;Gain of catalytic residue at L308 (P = 0.0509);.;.;.;.;.;.;

MVP

0.54

MPC

0.26

ClinPred

0.61

GERP RS

0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.11

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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14-92071010-C-G

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