14-92071010-C-CTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCA(p.Gly306GlnfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.040 (177 hom., cov: 20)
  • Exomes 𝑓: 0.063 (3324 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U: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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCA	p.Gly306GlnfsTer31	frameshift_variant	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCA	p.Gly306GlnfsTer31	frameshift_variant	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 5757 AN: 142366 Hom.: 178 Cov.: 20

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0580

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0395

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0474

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0633 AC: 82473 AN: 1302292 Hom.: 3324 Cov.: 92 AF XY: 0.0625 AC XY: 40704 AN XY: 651070

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0489

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.0546

Gnomad4 FIN exome AF: 0.0343

Gnomad4 NFE exome AF: 0.0704

Gnomad4 OTH exome AF: 0.0538

GnomAD4 genome AF: 0.0404 AC: 5753 AN: 142476 Hom.: 177 Cov.: 20 AF XY: 0.0386 AC XY: 2672 AN XY: 69216

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.0348

Gnomad4 SAS AF: 0.0527

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0581

Gnomad4 OTH AF: 0.0459

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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: rs1555397062; hg19: chr14-92537354;