Genetic Variant ATXN3:p.Gln304_Gln305del (chr14-92071010-CCTGCTG-C) – 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.910_915delCAGCAG(p.Gln304_Gln305del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,456,940 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATXN3
NM_004993.6 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.37

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:

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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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.910_915delCAGCAG	p.Gln304_Gln305del	conservative_inframe_deletion	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_915delCAGCAG	p.Gln304_Gln305del	conservative_inframe_deletion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.0000562

AC:

AN:

142396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000695

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000452

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000167

AC:

AN:

1314544

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

657294

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

27564

American (AMR)

AF:

0.0000987

AC:

AN:

40508

Ashkenazi Jewish (ASJ)

AF:

0.0000410

AC:

AN:

24398

East Asian (EAS)

AF:

0.00

AC:

AN:

37452

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79494

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

48908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5148

European-Non Finnish (NFE)

AF:

0.00000803

AC:

AN:

995966

Other (OTH)

AF:

0.00

AC:

AN:

55106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000562

AC:

AN:

142396

Hom.:

Cov.:

AF XY:

0.0000434

AC XY:

AN XY:

69104

show subpopulations

African (AFR)

AF:

0.000110

AC:

AN:

36200

American (AMR)

AF:

0.0000695

AC:

AN:

14398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4642

South Asian (SAS)

AF:

0.00

AC:

AN:

4314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

66422

Other (OTH)

AF:

0.00

AC:

AN:

1940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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:

0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=96/104

disease causing

(source)

Splicing

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

Publications

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14-92071010-CCTGCTGCTGCTG-CCTGCTG

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