14-92071009-C-CG

Position:

• chr14-92071009-C-CG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

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 Uncertain significance (★★).

• 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:4
• Conservation: PhyloP100: -0.802

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.916_917insC	p.Gly306AlafsTer12	frameshift_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.916_917insC	p.Gly306AlafsTer12	frameshift_variant	10/11		NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 31454 AN: 65716 Hom.: 3825 Cov.: 22 FAILED QC

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.: 50 AF XY: 0.361 AC XY: 141447 AN XY: 392262

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.426

Gnomad4 EAS exome AF: 0.427

Gnomad4 SAS exome AF: 0.380

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.479 AC: 31448 AN: 65706 Hom.: 3821 Cov.: 22 AF XY: 0.477 AC XY: 15334 AN XY: 32146

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.437

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.453

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.480

Alfa AF: 0.119 Hom.: 383

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

ATXN3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 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

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

LitVar

Other links and lift over

dbSNP: rs763461489; hg19: chr14-92537353; COSMIC: COSV61497794; COSMIC: COSV61497794;