14-92071010-CCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 50 hom., cov: 20)

Exomes 𝑓: 0.0055 ( 67 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004993.6

BP6

Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as Likely_benign. ClinVar VariationId is 3771181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0132 (1878/142482) while in subpopulation SAS AF = 0.0195 (84/4310). AF 95% confidence interval is 0.0161. There are 50 homozygotes in GnomAd4. There are 995 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 1878 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN3	NM_004993.6 link	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	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.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11		NM_004993.6	ENSP00000496695.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

1874

AN:

142372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0258

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.0307

Gnomad MID

AF:

0.0164

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.0165

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00551

AC:

7232

AN:

1312732

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

3981

AN XY:

656288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00526

AC:

145

AN:

27552

American (AMR)

AF:

0.00602

AC:

243

AN:

40398

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

363

AN:

24366

East Asian (EAS)

AF:

0.000107

AC:

AN:

37448

South Asian (SAS)

AF:

0.0100

AC:

798

AN:

79444

European-Finnish (FIN)

AF:

0.0250

AC:

1220

AN:

48778

Middle Eastern (MID)

AF:

0.00818

AC:

AN:

5134

European-Non Finnish (NFE)

AF:

0.00405

AC:

4026

AN:

994614

Other (OTH)

AF:

0.00711

AC:

391

AN:

54998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.399

Heterozygous variant carriers

358

716

1073

1431

1789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.0132

AC:

1878

AN:

142482

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

995

AN XY:

69220

show subpopulations

African (AFR)

AF:

0.0104

AC:

377

AN:

36312

American (AMR)

AF:

0.0110

AC:

159

AN:

14410

Ashkenazi Jewish (ASJ)

AF:

0.0258

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4634

South Asian (SAS)

AF:

0.0195

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.0307

AC:

303

AN:

9880

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0125

AC:

829

AN:

66400

Other (OTH)

AF:

0.0168

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATXN3: BS1 -

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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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