Genetic Variant ATXN3:p.Gly306GlnfsTer26 (chr14-92071010-C-CTG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_004993.6(ATXN3):c.915_916insCA(p.Gly306GlnfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,456,906 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00013 ( 13 hom. )

Consequence

ATXN3
NM_004993.6 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.168

Variant links:

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]

ATXN3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.915_916insCA	p.Gly306GlnfsTer26	frameshift_variant	Exon 10 of 11	ENST00000644486.2	NP_004984.2	P54252-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2 link	c.915_916insCA	p.Gly306GlnfsTer26	frameshift_variant	Exon 10 of 11		NM_004993.6	ENSP00000496695.1		P54252-2

Frequencies

GnomAD3 genomes

AF:

0.0000140

AC:

AN:

142396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000215

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

173

AN:

1314510

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

100

AN XY:

657280

show subpopulations

Gnomad4 AFR exome

AF:

0.000218

Gnomad4 AMR exome

AF:

0.0000247

Gnomad4 ASJ exome

AF:

0.000328

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.000377

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.0000726

GnomAD4 genome

AF:

0.0000140

AC:

AN:

142396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69104

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000215

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over