rs12896583

Positions:

• chr14-92071035-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164778.2(ATXN3):​c.406A>G​(p.Thr136Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T136?) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.034 (2 hom., cov: 0)
  • Exomes 𝑓: 0.19 (273 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_001164778.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.273

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.891A>G	p.Gln297Gln	synonymous_variant	10/11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.891A>G	p.Gln297Gln	synonymous_variant	10/11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 686 AN: 20002 Hom.: 2 Cov.: 0 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.: 47 AF XY: 0.180 AC XY: 45777 AN XY: 254024

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.: 2 Cov.: 0 AF XY: 0.0358 AC XY: 365 AN XY: 10184

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.: 63

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 12, 2014

- -

ATXN3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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

Other links and lift over

dbSNP: rs12896583; hg19: chr14-92537379; COSMIC: COSV61494112;