dbSNP rs910369: ATXN3:n.*1142G>T (chr14-92063938-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000359366.10(ATXN3):n.*1142G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 158,982 control chromosomes in the GnomAD database, including 5,581 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 ( 5390 hom., cov: 32)

Exomes 𝑓: 0.22 ( 191 hom. )

Consequence

ATXN3
ENST00000359366.10 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.404

Publications

20 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:

Genome browser will be placed here

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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.*382G>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2 link	c.*382G>T		3_prime_UTR_variant	Exon 11 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39826

AN:

151826

Hom.:

5374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.252

GnomAD4 exome

AF:

0.219

AC:

1542

AN:

7038

Hom.:

191

Cov.:

AF XY:

0.228

AC XY:

832

AN XY:

3656

show subpopulations

African (AFR)

AF:

0.321

AC:

AN:

American (AMR)

AF:

0.115

AC:

AN:

608

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

AN:

104

East Asian (EAS)

AF:

0.351

AC:

AN:

248

South Asian (SAS)

AF:

0.287

AC:

188

AN:

654

European-Finnish (FIN)

AF:

0.226

AC:

AN:

380

Middle Eastern (MID)

AF:

0.300

AC:

AN:

European-Non Finnish (NFE)

AF:

0.211

AC:

985

AN:

4658

Other (OTH)

AF:

0.216

AC:

AN:

320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.262

AC:

39878

AN:

151944

Hom.:

5390

Cov.:

AF XY:

0.263

AC XY:

19512

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.311

AC:

12885

AN:

41436

American (AMR)

AF:

0.186

AC:

2847

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1084

AN:

3470

East Asian (EAS)

AF:

0.356

AC:

1842

AN:

5176

South Asian (SAS)

AF:

0.350

AC:

1687

AN:

4822

European-Finnish (FIN)

AF:

0.233

AC:

2450

AN:

10522

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.239

AC:

16240

AN:

67932

Other (OTH)

AF:

0.253

AC:

533

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1491

2982

4474

5965

7456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.232

Hom.:

5690

Bravo

AF:

0.260

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

-0.92

CADD

Benign

0.40

(source)

DANN

Benign

0.35

PhyloP100

-0.40

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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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