Genetic Variant ATXN3:p.Gln304_Gln305dup (chr14-92071010-C-CCTGCTG) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_004993.6(ATXN3):c.910_915dupCAGCAG(p.Gln304_Gln305dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,456,778 control chromosomes in the GnomAD database, including 43 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00062 ( 43 hom. )

Consequence

ATXN3
NM_004993.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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: Benign. The variant received -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004993.6

BP6

Variant 14-92071010-C-CCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 599464.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.910_915dupCAGCAG	p.Gln304_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.910_915dupCAGCAG	p.Gln304_Gln305dup	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.000449

AC:

AN:

142396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000764

Gnomad ASJ

AF:

0.000586

Gnomad EAS

AF:

0.000431

Gnomad SAS

AF:

0.00162

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000512

Gnomad OTH

AF:

0.000515

GnomAD4 exome

AF:

0.000618

AC:

812

AN:

1314272

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

424

AN XY:

657142

show subpopulations

African (AFR)

AF:

0.000545

AC:

AN:

27502

American (AMR)

AF:

0.000864

AC:

AN:

40496

Ashkenazi Jewish (ASJ)

AF:

0.000164

AC:

AN:

24396

East Asian (EAS)

AF:

0.000107

AC:

AN:

37452

South Asian (SAS)

AF:

0.00138

AC:

110

AN:

79488

European-Finnish (FIN)

AF:

0.0000409

AC:

AN:

48902

Middle Eastern (MID)

AF:

0.00524

AC:

AN:

5148

European-Non Finnish (NFE)

AF:

0.000577

AC:

575

AN:

995786

Other (OTH)

AF:

0.000726

AC:

AN:

55102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000449

AC:

AN:

142506

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

AN XY:

69232

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

36314

American (AMR)

AF:

0.000763

AC:

AN:

14414

Ashkenazi Jewish (ASJ)

AF:

0.000586

AC:

AN:

3412

East Asian (EAS)

AF:

0.000432

AC:

AN:

4634

South Asian (SAS)

AF:

0.00162

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000512

AC:

AN:

66414

Other (OTH)

AF:

0.000510

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Bravo

AF:

0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 03, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Normal variation in repetative sequence

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.17

Mutation Taster

=78/22

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-CCTGCTGCTGCTGCTGCTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over