16-78108411-G-T

Variant names:

Variant summary

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

The NM_016373.4(WWOX):c.108-12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,559,636 control chromosomes in the GnomAD database, including 37,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 8339 hom., cov: 31)

Exomes 𝑓: 0.29 ( 29345 hom. )

Consequence

WWOX
NM_016373.4 intron

Scores

Splicing: ADA: 0.00002093

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.633

Publications

4 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=-0.93).

BP6

Variant 16-78108411-G-T is Benign according to our data. Variant chr16-78108411-G-T is described in ClinVar as Benign. ClinVar VariationId is 260737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WWOX	NM_016373.4	MANE Select	c.108-12G>T	intron	N/A	NP_057457.1	Q9NZC7-1
WWOX	NM_001291997.2		c.-167-1367G>T	intron	N/A	NP_001278926.1
WWOX	NM_130791.5		c.108-12G>T	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.108-12G>T	intron	N/A	ENSP00000457230.1	Q9NZC7-1
WWOX	ENST00000408984.7	TSL:1	c.108-12G>T	intron	N/A	ENSP00000386161.3	Q9NZC7-2
WWOX	ENST00000402655.6	TSL:1	c.108-12G>T	intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

50201

AN:

148400

Hom.:

8333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.302

GnomAD2 exomes

AF:

0.262

AC:

62485

AN:

238360

AF XY:

0.260

show subpopulations

Gnomad AFR exome

AF:

0.332

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.281

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.283

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.287

AC:

404344

AN:

1411128

Hom.:

29345

Cov.:

AF XY:

0.284

AC XY:

199828

AN XY:

702786

show subpopulations

African (AFR)

AF:

0.358

AC:

11006

AN:

30768

American (AMR)

AF:

0.225

AC:

9603

AN:

42670

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

7144

AN:

25320

East Asian (EAS)

AF:

0.189

AC:

7395

AN:

39050

South Asian (SAS)

AF:

0.221

AC:

18548

AN:

83956

European-Finnish (FIN)

AF:

0.297

AC:

15329

AN:

51674

Middle Eastern (MID)

AF:

0.231

AC:

1300

AN:

5622

European-Non Finnish (NFE)

AF:

0.296

AC:

317580

AN:

1073890

Other (OTH)

AF:

0.283

AC:

16439

AN:

58178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

14269

28537

42806

57074

71343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11286

22572

33858

45144

56430

<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:

0.338

AC:

50236

AN:

148508

Hom.:

8339

Cov.:

AF XY:

0.334

AC XY:

24253

AN XY:

72522

show subpopulations

African (AFR)

AF:

0.379

AC:

14646

AN:

38670

American (AMR)

AF:

0.283

AC:

4274

AN:

15110

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

1160

AN:

3466

East Asian (EAS)

AF:

0.219

AC:

1127

AN:

5152

South Asian (SAS)

AF:

0.250

AC:

1203

AN:

4804

European-Finnish (FIN)

AF:

0.345

AC:

3555

AN:

10308

Middle Eastern (MID)

AF:

0.248

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.344

AC:

23277

AN:

67720

Other (OTH)

AF:

0.299

AC:

621

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1528

3055

4583

6110

7638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.229

Hom.:

1517

Bravo

AF:

0.334

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal recessive spinocerebellar ataxia 12 (1)

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

Developmental and epileptic encephalopathy, 28 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.40

(source)

DANN

Benign

0.27

PhyloP100

-0.63

Mutation Taster

=48/52

disease causing (long InDel)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0060

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