rs8050128

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130791.5(WWOX):c.517-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,581,356 control chromosomes in the GnomAD database, including 166,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 16822 hom., cov: 32)

Exomes 𝑓: 0.45 ( 149745 hom. )

Consequence

WWOX
NM_130791.5 splice_region, intron

Scores

Splicing: ADA: 0.00002942

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.736

Publications

15 publications found

Variant links:

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WWOX Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive spinocerebellar ataxia 12
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WWOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 16-78278600-C-A is Benign according to our data. Variant chr16-78278600-C-A is described in ClinVar as Benign. ClinVar VariationId is 586944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130791.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WWOX	NM_016373.4	MANE Select	c.517-108260C>A	intron	N/A	NP_057457.1	Q9NZC7-1
WWOX	NM_001291997.2		c.178-108260C>A	intron	N/A	NP_001278926.1
WWOX	NM_130791.5		c.517-3C>A	splice_region intron	N/A	NP_570607.1	Q9NZC7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.517-108260C>A	intron	N/A	ENSP00000457230.1	Q9NZC7-1
WWOX	ENST00000408984.7	TSL:1	c.517-108260C>A	intron	N/A	ENSP00000386161.3	Q9NZC7-2
WWOX	ENST00000402655.6	TSL:1	c.409+163446C>A	intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

70874

AN:

151814

Hom.:

16799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.456

Gnomad ASJ

AF:

0.538

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.468

GnomAD2 exomes

AF:

0.449

AC:

109000

AN:

242750

AF XY:

0.446

show subpopulations

Gnomad AFR exome

AF:

0.513

Gnomad AMR exome

AF:

0.427

Gnomad ASJ exome

AF:

0.537

Gnomad EAS exome

AF:

0.478

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.454

Gnomad OTH exome

AF:

0.461

GnomAD4 exome

AF:

0.451

AC:

644353

AN:

1429424

Hom.:

149745

Cov.:

AF XY:

0.449

AC XY:

319603

AN XY:

711194

show subpopulations

African (AFR)

AF:

0.520

AC:

17239

AN:

33174

American (AMR)

AF:

0.430

AC:

18973

AN:

44158

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

13777

AN:

25658

East Asian (EAS)

AF:

0.471

AC:

18514

AN:

39308

South Asian (SAS)

AF:

0.406

AC:

34302

AN:

84422

European-Finnish (FIN)

AF:

0.417

AC:

21999

AN:

52724

Middle Eastern (MID)

AF:

0.532

AC:

3028

AN:

5688

European-Non Finnish (NFE)

AF:

0.451

AC:

489215

AN:

1085106

Other (OTH)

AF:

0.461

AC:

27306

AN:

59186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

15417

30834

46252

61669

77086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14592

29184

43776

58368

72960

<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:

0.467

AC:

70939

AN:

151932

Hom.:

16822

Cov.:

AF XY:

0.464

AC XY:

34454

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.518

AC:

21430

AN:

41390

American (AMR)

AF:

0.456

AC:

6960

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.538

AC:

1869

AN:

3472

East Asian (EAS)

AF:

0.476

AC:

2455

AN:

5162

South Asian (SAS)

AF:

0.403

AC:

1943

AN:

4824

European-Finnish (FIN)

AF:

0.418

AC:

4407

AN:

10548

Middle Eastern (MID)

AF:

0.565

AC:

166

AN:

294

European-Non Finnish (NFE)

AF:

0.447

AC:

30370

AN:

67938

Other (OTH)

AF:

0.476

AC:

1008

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1927

3854

5782

7709

9636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<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:

0.462

Hom.:

8176

Bravo

AF:

0.475

Asia WGS

AF:

0.481

AC:

1666

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

WWOX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

5.6

(source)

DANN

Benign

0.45

PhyloP100

0.74

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over