14-92071010-CCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG
• rs193922928
• NM_004993.6:c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln297_Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5355 hom., cov: 20)
  • Exomes 𝑓: 0.27 (38089 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -10 ACMG points.

• BP6: Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as [Benign]. Clinvar id is 1050334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln297_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln297_Gln305dup	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 35384 AN: 142178 Hom.: 5352 Cov.: 20

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.277

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.272 AC: 343134 AN: 1261568 Hom.: 38089 Cov.: 92 AF XY: 0.269 AC XY: 169994 AN XY: 631004

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.00910

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.249 AC: 35403 AN: 142284 Hom.: 5355 Cov.: 20 AF XY: 0.250 AC XY: 17288 AN XY: 69096

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.281

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Nov 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATXN3 p.Ala22_Gly23ins9 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 nine 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;