Variant 14-92071010-CCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.069 ( 524 hom., cov: 20)

Exomes 𝑓: 0.025 ( 221 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.168

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 -9 ACMG points.

BP6

Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as [Likely_benign]. Clinvar id is 1050021.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6 linkuse as main transcript	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2 linkuse as main transcript	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11		NM_004993.6	ENSP00000496695	P1	P54252-2

Frequencies

GnomAD3 genomes

AF:

0.0695

AC:

9883

AN:

142238

Hom.:

524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0488

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0660

Gnomad EAS

AF:

0.00409

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.0230

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.0680

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0249

AC:

32736

AN:

1312834

Hom.:

221

Cov.:

AF XY:

0.0263

AC XY:

17266

AN XY:

656116

show subpopulations

Gnomad4 AFR exome

AF:

0.0207

Gnomad4 AMR exome

AF:

0.0433

Gnomad4 ASJ exome

AF:

0.0335

Gnomad4 EAS exome

AF:

0.00192

Gnomad4 SAS exome

AF:

0.0223

Gnomad4 FIN exome

AF:

0.0560

Gnomad4 NFE exome

AF:

0.0230

Gnomad4 OTH exome

AF:

0.0358

GnomAD4 genome

AF:

0.0695

AC:

9888

AN:

142348

Hom.:

524

Cov.:

AF XY:

0.0696

AC XY:

4814

AN XY:

69142

show subpopulations

Gnomad4 AFR

AF:

0.0488

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.0660

Gnomad4 EAS

AF:

0.00410

Gnomad4 SAS

AF:

0.0353

Gnomad4 FIN

AF:

0.0723

Gnomad4 NFE

AF:

0.0801

Gnomad4 OTH

AF:

0.0678

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATXN3 p.Ala22_Gly23ins13 variant was identified in dbSNP (ID: rs763541221), ClinVar, Cosmic and LOVD 3.0. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion resulting in the inclusion of 13 CAG repeats. The (CAG)n repeat within the ATXN3 gene was found to cause Machado-Joseph disease at 73-78 repeats while 14-40 repeats was considered the normal range (Limprasert_1996_PMID: 8824876). More recent studies have suggested 52 to 86 repeats as pathogenic (GeneReviews). This CAG repeat expansion would fall within the normal range and this variant is predicted to be a polymorphism by MutationTaster. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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