16-78432717-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_016373.4(WWOX):c.1021C>A(p.Leu341Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L341L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.57

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05016288).

BP6

Variant 16-78432717-C-A is Benign according to our data. Variant chr16-78432717-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 567538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000591 (90/152284) while in subpopulation AFR AF = 0.002 (83/41542). AF 95% confidence interval is 0.00165. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1021C>A	p.Leu341Met	missense	Exon 8 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.682C>A	p.Leu228Met	missense	Exon 7 of 8	NP_001278926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1021C>A	p.Leu341Met	missense	Exon 8 of 9	ENSP00000457230.1	Q9NZC7-1
WWOX	ENST00000408984.7	TSL:1	c.1021C>A	p.Leu341Met	missense	Exon 8 of 10	ENSP00000386161.3	Q9NZC7-2
WWOX	ENST00000402655.6	TSL:1	c.409+317563C>A		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000160

AC:

AN:

249566

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.000149

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000591

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41542

American (AMR)

AF:

0.000457

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000269

Hom.:

Bravo

AF:

0.000763

ESP6500AA

AF:

0.00195

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000190

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.050

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.4

PhyloP100

7.6

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.46

Sift

Benign

0.095

Sift4G

Benign

0.11

Polyphen

0.63

Vest4

0.66

MVP

0.90

ClinPred

0.029

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.81

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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