14-92071010-C-CCTGCTGCTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAG(p.Gln303_Gln305dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,456,608 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00033 (38 hom.)
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAG	p.Gln303_Gln305dup	inframe_insertion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAG	p.Gln303_Gln305dup	inframe_insertion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 44 AN: 142394 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000271

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000331 AC: 435 AN: 1314104 Hom.: 38 Cov.: 92 AF XY: 0.000282 AC XY: 185 AN XY: 657086

Gnomad4 AFR exome AF: 0.000873

Gnomad4 AMR exome AF: 0.000815

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.000164

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.000345

GnomAD4 genome AF: 0.000309 AC: 44 AN: 142504 Hom.: 0 Cov.: 20 AF XY: 0.000289 AC XY: 20 AN XY: 69230

Gnomad4 AFR AF: 0.000303

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000271

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

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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: rs193922928; hg19: chr14-92537354;