Genetic Variant ATXN3:p.Gln300_Gln305dup (chr14-92071010-C-CCTGCTGCTGCTGCTGCTG) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_004993.6(ATXN3):c.898_915dupCAGCAGCAGCAGCAGCAG(p.Gln300_Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0047 ( 11 hom., cov: 20)

Exomes 𝑓: 0.0046 ( 232 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.168

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004993.6

BS2

High AC in GnomAd4 at 668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.898_915dupCAGCAGCAGCAGCAGCAG	p.Gln300_Gln305dup	conservative_inframe_insertion	Exon 10 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.898_915dupCAGCAGCAGCAGCAGCAG	p.Gln300_Gln305dup	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

670

AN:

142388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00713

Gnomad AMI

AF:

0.00682

Gnomad AMR

AF:

0.00319

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000464

Gnomad FIN

AF:

0.00739

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00411

Gnomad OTH

AF:

0.00619

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00460

AC:

6047

AN:

1314098

Hom.:

232

Cov.:

AF XY:

0.00447

AC XY:

2935

AN XY:

657034

show subpopulations

African (AFR)

AF:

0.00842

AC:

232

AN:

27542

American (AMR)

AF:

0.00291

AC:

118

AN:

40504

Ashkenazi Jewish (ASJ)

AF:

0.000328

AC:

AN:

24398

East Asian (EAS)

AF:

0.000107

AC:

AN:

37440

South Asian (SAS)

AF:

0.000869

AC:

AN:

79356

European-Finnish (FIN)

AF:

0.00564

AC:

276

AN:

48906

Middle Eastern (MID)

AF:

0.00117

AC:

AN:

5148

European-Non Finnish (NFE)

AF:

0.00508

AC:

5056

AN:

995720

Other (OTH)

AF:

0.00505

AC:

278

AN:

55084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

183

366

548

731

914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00469

AC:

668

AN:

142498

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

311

AN XY:

69230

show subpopulations

African (AFR)

AF:

0.00708

AC:

257

AN:

36314

American (AMR)

AF:

0.00319

AC:

AN:

14414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4634

South Asian (SAS)

AF:

0.000464

AC:

AN:

4308

European-Finnish (FIN)

AF:

0.00739

AC:

AN:

9880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00410

AC:

272

AN:

66412

Other (OTH)

AF:

0.00612

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.17

Mutation Taster

=80/20

polymorphism

(source)

Splicing

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

Publications

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14-92071010-CCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

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