rs763461489

chr14-92071009-C-CAchr14-92071009-C-CACTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGchr14-92071009-C-CGCTchr14-92071009-C-CGCTGCTchr14-92071009-C-CGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGchr14-92071009-C-CGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTchr14-92071009-C-CTchr14-92071009-C-CTCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

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

The NM_004993.6(ATXN3):c.916_917insT(p.Gly306ValfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000907 in 66,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000091 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000038 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802

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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.916_917insT	p.Gly306ValfsTer12	frameshift_variant	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.916_917insT	p.Gly306ValfsTer12	frameshift_variant	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000907 AC: 6 AN: 66138 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000385 AC: 3 AN: 779474 Hom.: 1 Cov.: 50 AF XY: 0.00000508 AC XY: 2 AN XY: 393814

Gnomad4 AFR exome AF: 0.0000828

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000396

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000907 AC: 6 AN: 66138 Hom.: 0 Cov.: 22 AF XY: 0.0000928 AC XY: 3 AN XY: 32332

Gnomad4 AFR AF: 0.000514

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs763461489; hg19: chr14-92537353;