chr14-92071010-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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. In-silico tool predicts a benign outcome for this variant. 13/19 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. G306?) has been classified as Benign.

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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. Variant chr14-92071010-C-G is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 809 AD gene.

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

Gnomad4 AFR exome

AF:

0.0524

Gnomad4 AMR exome

AF:

0.0305

Gnomad4 ASJ exome

AF:

0.0454

Gnomad4 EAS exome

AF:

0.0541

Gnomad4 SAS exome

AF:

0.0592

Gnomad4 FIN exome

AF:

0.0201

Gnomad4 NFE exome

AF:

0.0382

Gnomad4 OTH exome

AF:

0.0414

GnomAD4 genome

AF:

0.00568

AC:

809

AN:

142372

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

393

AN XY:

69160

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.00312

Gnomad4 ASJ

AF:

0.00234

Gnomad4 EAS

AF:

0.0152

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.00121

Gnomad4 NFE

AF:

0.00245

Gnomad4 OTH

AF:

0.00715

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over