14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

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

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln298_Gln305dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (563 hom., cov: 20)
  • Exomes 𝑓: 0.043 (2021 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter 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 -10 ACMG points.

• BP6: Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as [Benign]. Clinvar id is 3055415.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln298_Gln305dup	inframe_insertion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln298_Gln305dup	inframe_insertion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 5960 AN: 142264 Hom.: 558 Cov.: 20

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00278

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0230

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.0237

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0427 AC: 53693 AN: 1256914 Hom.: 2021 Cov.: 92 AF XY: 0.0411 AC XY: 25806 AN XY: 627840

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.0639

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.000721

Gnomad4 SAS exome AF: 0.0302

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.0424

Gnomad4 OTH exome AF: 0.0417

GnomAD4 genome AF: 0.0420 AC: 5976 AN: 142374 Hom.: 563 Cov.: 20 AF XY: 0.0408 AC XY: 2824 AN XY: 69154

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00302

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.0235

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATXN3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2020

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

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;