Genetic Variant ATXN3:n.*911G>A (chr14-92064169-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004993.6(ATXN3):c.*151G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 525,556 control chromosomes in the GnomAD database, including 18,866 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5377 hom., cov: 33)

Exomes 𝑓: 0.26 ( 13489 hom. )

Consequence

ATXN3
NM_004993.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.10

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

Machado-Joseph disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Machado-Joseph disease type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Machado-Joseph disease type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Machado-Joseph disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATXN3 links:

ENSG00000303901 (HGNC:):

ENSG00000303901 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.*151G>A		3_prime_UTR_variant	Exon 11 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.*151G>A		3_prime_UTR_variant	Exon 11 of 11		NM_004993.6	ENSP00000496695.1		P54252-2

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39784

AN:

151924

Hom.:

5361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.252

GnomAD4 exome

AF:

0.260

AC:

97157

AN:

373514

Hom.:

13489

Cov.:

AF XY:

0.264

AC XY:

51596

AN XY:

195626

show subpopulations

African (AFR)

AF:

0.319

AC:

3166

AN:

9934

American (AMR)

AF:

0.172

AC:

2246

AN:

13082

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

3742

AN:

11594

East Asian (EAS)

AF:

0.402

AC:

10688

AN:

26574

South Asian (SAS)

AF:

0.354

AC:

9325

AN:

26318

European-Finnish (FIN)

AF:

0.220

AC:

8307

AN:

37690

Middle Eastern (MID)

AF:

0.282

AC:

464

AN:

1646

European-Non Finnish (NFE)

AF:

0.239

AC:

53794

AN:

225320

Other (OTH)

AF:

0.254

AC:

5425

AN:

21356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

3306

6611

9917

13222

16528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.262

AC:

39836

AN:

152042

Hom.:

5377

Cov.:

AF XY:

0.262

AC XY:

19489

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.310

AC:

12842

AN:

41470

American (AMR)

AF:

0.186

AC:

2834

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1084

AN:

3470

East Asian (EAS)

AF:

0.357

AC:

1846

AN:

5174

South Asian (SAS)

AF:

0.350

AC:

1686

AN:

4822

European-Finnish (FIN)

AF:

0.233

AC:

2461

AN:

10570

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16239

AN:

67966

Other (OTH)

AF:

0.253

AC:

534

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1516

3032

4549

6065

7581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.213

Hom.:

1652

Bravo

AF:

0.259

Asia WGS

AF:

0.359

AC:

1248

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.83

(source)

DANN

Benign

0.73

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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14-92064169-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over