Genetic Variant ATXN3:p.Gln301_Gln305dup (chr14-92071010-C-CCTGCTGCTGCTGCTG) – 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.901_915dupCAGCAGCAGCAGCAG(p.Gln301_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. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0033 ( 11 hom., cov: 20)

Exomes 𝑓: 0.0010 ( 33 hom. )

Failed GnomAD Quality Control

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-CCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 2644469.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 470 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.901_915dupCAGCAGCAGCAGCAG	p.Gln301_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.901_915dupCAGCAGCAGCAGCAG	p.Gln301_Gln305dup	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

468

AN:

142394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00928

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00234

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000927

Gnomad FIN

AF:

0.000304

Gnomad MID

AF:

0.00658

Gnomad NFE

AF:

0.000933

Gnomad OTH

AF:

0.00155

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00104

AC:

1369

AN:

1314286

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

684

AN XY:

657180

show subpopulations

African (AFR)

AF:

0.0104

AC:

287

AN:

27552

American (AMR)

AF:

0.00148

AC:

AN:

40506

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

24394

East Asian (EAS)

AF:

0.00

AC:

AN:

37452

South Asian (SAS)

AF:

0.00107

AC:

AN:

79488

European-Finnish (FIN)

AF:

0.000736

AC:

AN:

48900

Middle Eastern (MID)

AF:

0.00291

AC:

AN:

5148

European-Non Finnish (NFE)

AF:

0.000749

AC:

746

AN:

995746

Other (OTH)

AF:

0.00176

AC:

AN:

55100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00330

AC:

470

AN:

142504

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

236

AN XY:

69232

show subpopulations

African (AFR)

AF:

0.00931

AC:

338

AN:

36312

American (AMR)

AF:

0.00347

AC:

AN:

14414

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4634

South Asian (SAS)

AF:

0.000928

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.000304

AC:

AN:

9884

Middle Eastern (MID)

AF:

0.00709

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000934

AC:

AN:

66414

Other (OTH)

AF:

0.00153

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

114

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATXN3: BS1, BS2 -

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-CCTGCTGCTGCTGCTGCTGCTGCTGCTG

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