rs141993435

Positions:

• chr14-92071041-CTTT-C

Variant summary

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

The NM_004993.6(ATXN3):​c.882_884del​(p.Lys295del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,601,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q294Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: ATXN3 NM_004993.6 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.882_884del	p.Lys295del	inframe_deletion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.882_884del	p.Lys295del	inframe_deletion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000337 AC: 5 AN: 148196 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

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 AF: 0.000702 AC: 1020 AN: 1452888 Hom.: 0 AF XY: 0.000664 AC XY: 480 AN XY: 722852

Gnomad4 AFR exome AF: 0.000814

Gnomad4 AMR exome AF: 0.000678

Gnomad4 ASJ exome AF: 0.000538

Gnomad4 EAS exome AF: 0.000456

Gnomad4 SAS exome AF: 0.000677

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.000578

Gnomad4 OTH exome AF: 0.000782

GnomAD4 genome AF: 0.0000337 AC: 5 AN: 148298 Hom.: 0 Cov.: 0 AF XY: 0.0000414 AC XY: 3 AN XY: 72456

Gnomad4 AFR AF: 0.000101

Gnomad4 AMR AF: 0.0000675

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs141993435; hg19: chr14-92537385;