Genetic Variant ATXN3:p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln (chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) 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 0.039 ( 202 hom., cov: 20)

Exomes 𝑓: 0.034 ( 4293 hom. )

Failed GnomAD Quality Control

Consequence

ATXN3
NM_004993.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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 -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004993.6

BP6

Variant 14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 218660.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0391 (5565/142438) while in subpopulation NFE AF = 0.0474 (3144/66386). AF 95% confidence interval is 0.046. There are 202 homozygotes in GnomAd4. There are 2539 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAd4 at 5565 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN3	NM_004993.6	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
ATXN3	NM_001127696.2		c.870_871insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln290_Gly291insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1	P54252-4
ATXN3	NM_001127697.3		c.762_763insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln254_Gly255insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 8 of 9	NP_001121169.2	A0A0A0MS38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN3	ENST00000644486.2	MANE Select	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1	P54252-2
ATXN3	ENST00000532032.5	TSL:1	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1	P54252-1
ATXN3	ENST00000503767.5	TSL:1	c.870_871insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln290_Gly291insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1	P54252-4

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5555

AN:

142328

Hom.:

200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.0193

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.0223

Gnomad EAS

AF:

0.0248

Gnomad SAS

AF:

0.0318

Gnomad FIN

AF:

0.0229

Gnomad MID

AF:

0.0296

Gnomad NFE

AF:

0.0474

Gnomad OTH

AF:

0.0346

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0336

AC:

44006

AN:

1309066

Hom.:

4293

Cov.:

AF XY:

0.0340

AC XY:

22226

AN XY:

654526

show subpopulations

African (AFR)

AF:

0.0342

AC:

937

AN:

27436

American (AMR)

AF:

0.0208

AC:

842

AN:

40430

Ashkenazi Jewish (ASJ)

AF:

0.0221

AC:

538

AN:

24320

East Asian (EAS)

AF:

0.0308

AC:

1153

AN:

37428

South Asian (SAS)

AF:

0.0283

AC:

2245

AN:

79248

European-Finnish (FIN)

AF:

0.0250

AC:

1220

AN:

48852

Middle Eastern (MID)

AF:

0.0203

AC:

104

AN:

5134

European-Non Finnish (NFE)

AF:

0.0355

AC:

35183

AN:

991250

Other (OTH)

AF:

0.0325

AC:

1784

AN:

54968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

1604

3209

4813

6418

8022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

954

1908

2862

3816

4770

<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:

0.0391

AC:

5565

AN:

142438

Hom.:

202

Cov.:

AF XY:

0.0367

AC XY:

2539

AN XY:

69194

show subpopulations

African (AFR)

AF:

0.0381

AC:

1381

AN:

36290

American (AMR)

AF:

0.0273

AC:

394

AN:

14408

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

AN:

3412

East Asian (EAS)

AF:

0.0248

AC:

115

AN:

4632

South Asian (SAS)

AF:

0.0316

AC:

136

AN:

4308

European-Finnish (FIN)

AF:

0.0229

AC:

226

AN:

9880

Middle Eastern (MID)

AF:

0.0319

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0474

AC:

3144

AN:

66386

Other (OTH)

AF:

0.0342

AC:

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

224

448

672

896

1120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0228

Hom.:

345

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over