Genetic Variant ATXN8OS:n.1140_1148delTGCTGCTGC (chr13-70139383-ACTGCTGCTG-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000414504.6(ATXN8OS):n.1140_1148delTGCTGCTGC variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0061 ( 3 hom., cov: 0)

Exomes 𝑓: 0.014 ( 334 hom. )

Failed GnomAD Quality Control

Consequence

ATXN8OS
ENST00000414504.6 splice_region, non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.190

Publications

0 publications found

Variant links:

Genes affected

ATXN8OS (HGNC:10561): (ATXN8 opposite strand lncRNA) This gene is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not itself appear to be protein coding. A TAC/TGC trinucleotide repeat expansion that is incorporated into this gene transcript, but not the KLHL1 transcript, causes spinocerebellar ataxia type 8. Presumably the expansion interferes with normal antisense function of this transcript. [provided by RefSeq, Oct 2008]

ATXN8OS Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ATXN8OS links:

ENSG00000288330 (HGNC:32925):

ENSG00000288330 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 666 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
ATXN8OS	NR_002717.3 link	n.932_940delTGCTGCTGC	non_coding_transcript_exon_variant	Exon 5 of 5
ATXN8OS	NR_185834.1 link	n.454-7934_454-7926delTGCTGCTGC	intron_variant	Intron 3 of 4
ATXN8OS	NR_185835.1 link	n.454-7934_454-7926delTGCTGCTGC	intron_variant	Intron 3 of 6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
ATXN8OS	ENST00000414504.6 link	n.1140_1148delTGCTGCTGC	splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	5
ENSG00000288330	ENST00000673087.1 link	n.40_48delCAGCAGCAG	non_coding_transcript_exon_variant	Exon 1 of 1
ATXN8OS	ENST00000756272.1 link	n.805_813delTGCTGCTGC	non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.00610

AC:

665

AN:

109066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00906

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.0422

Gnomad EAS

AF:

0.00961

Gnomad SAS

AF:

0.00608

Gnomad FIN

AF:

0.000767

Gnomad MID

AF:

0.0156

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00639

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0135

AC:

4567

AN:

338096

Hom.:

334

AF XY:

0.0145

AC XY:

2601

AN XY:

179838

show subpopulations

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

African (AFR)

AF:

0.00918

AC:

AN:

7846

American (AMR)

AF:

0.0240

AC:

430

AN:

17904

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

467

AN:

11486

East Asian (EAS)

AF:

0.00472

AC:

116

AN:

24554

South Asian (SAS)

AF:

0.0313

AC:

802

AN:

25662

European-Finnish (FIN)

AF:

0.00529

AC:

110

AN:

20796

Middle Eastern (MID)

AF:

0.0203

AC:

AN:

1528

European-Non Finnish (NFE)

AF:

0.0109

AC:

2270

AN:

209112

Other (OTH)

AF:

0.0140

AC:

269

AN:

19208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

188

376

565

753

941

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:

0.00610

AC:

666

AN:

109096

Hom.:

Cov.:

AF XY:

0.00578

AC XY:

304

AN XY:

52640

show subpopulations

African (AFR)

AF:

0.00916

AC:

223

AN:

24350

American (AMR)

AF:

0.00301

AC:

AN:

10970

Ashkenazi Jewish (ASJ)

AF:

0.0422

AC:

120

AN:

2844

East Asian (EAS)

AF:

0.00938

AC:

AN:

3730

South Asian (SAS)

AF:

0.00609

AC:

AN:

3612

European-Finnish (FIN)

AF:

0.000767

AC:

AN:

6516

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00395

AC:

216

AN:

54654

Other (OTH)

AF:

0.00636

AC:

AN:

1416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

112

140

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

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

Computational scores

Splicing

Publications

Other links and lift over