14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

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
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.168

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 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	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 9883 AN: 142238 Hom.: 524 Cov.: 20

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.: 92 AF XY: 0.0263 AC XY: 17266 AN XY: 656116

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.: 20 AF XY: 0.0696 AC XY: 4814 AN XY: 69142

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

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354;