dbSNP rs10514443: WWOX:c.1056+329236G>A (chr16-78761988-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016373.4(WWOX):c.1056+329236G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 152,142 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.045 ( 347 hom., cov: 33)

Consequence

WWOX
NM_016373.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.119

Publications

2 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.1056+329236G>A		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 link	c.717+329236G>A		intron_variant	Intron 7 of 7		NP_001278926.1	Q9NZC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.1056+329236G>A		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

6837

AN:

152024

Hom.:

344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0501

Gnomad FIN

AF:

0.00463

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.0335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0451

AC:

6860

AN:

152142

Hom.:

347

Cov.:

AF XY:

0.0448

AC XY:

3329

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.125

AC:

5178

AN:

41486

American (AMR)

AF:

0.0213

AC:

326

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.0161

AC:

AN:

5170

South Asian (SAS)

AF:

0.0505

AC:

243

AN:

4810

European-Finnish (FIN)

AF:

0.00463

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

866

AN:

67996

Other (OTH)

AF:

0.0331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

314

628

943

1257

1571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0269

Hom.:

Bravo

AF:

0.0488

Asia WGS

AF:

0.0380

AC:

134

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.51

(source)

DANN

Benign

0.59

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over