Genetic Variant NM_004993.6:c.891A>G (chr14-92071035-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_004993.6(ATXN3):c.891A>G(p.Gln297Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 2 hom., cov: 0)

Exomes 𝑓: 0.19 ( 273 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.273

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 14-92071035-T-C is Benign according to our data. Variant chr14-92071035-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-92071035-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.273 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.891A>G	p.Gln297Gln	synonymous_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.891A>G	p.Gln297Gln	synonymous_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1		P54252-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

686

AN:

20002

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0128

Gnomad EAS

AF:

0.0167

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.00542

Gnomad MID

AF:

0.0294

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0504

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.188

AC:

94896

AN:

503886

Hom.:

273

Cov.:

AF XY:

0.180

AC XY:

45777

AN XY:

254024

show subpopulations

Gnomad4 AFR exome

AF:

0.239

Gnomad4 AMR exome

AF:

0.151

Gnomad4 ASJ exome

AF:

0.143

Gnomad4 EAS exome

AF:

0.0741

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.210

Gnomad4 OTH exome

AF:

0.170

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0344

AC:

689

AN:

20016

Hom.:

Cov.:

AF XY:

0.0358

AC XY:

365

AN XY:

10184

show subpopulations

Gnomad4 AFR

AF:

0.119

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0128

Gnomad4 EAS

AF:

0.0168

Gnomad4 SAS

AF:

0.0146

Gnomad4 FIN

AF:

0.00542

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.0543

Alfa

AF:

0.0450

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 21, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 12, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATXN3-related disorder

Benign:1

Oct 31, 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

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.42

DANN

Benign

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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