16-79211923-G-T

Variant names:

Variant summary

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

The ENST00000402655.6(WWOX):c.725G>T(p.Ser242Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,541,148 control chromosomes in the GnomAD database, including 221,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17163 hom., cov: 33)

Exomes 𝑓: 0.53 ( 204174 hom. )

Consequence

WWOX
ENST00000402655.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.90

Publications

42 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 links:

MAF (HGNC:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

MAF Gene-Disease associations (from GenCC):

Ayme-Gripp syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
cataract 21 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cerulean cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fine-Lubinsky syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MAF links:

ENSG00000261722 (HGNC:):

ENSG00000261722 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 (MetaRNN=1.7422438E-4).

BP6

Variant 16-79211923-G-T is Benign according to our data. Variant chr16-79211923-G-T is described in ClinVar as Benign. ClinVar VariationId is 1247128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402655.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.*127G>T		3_prime_UTR	Exon 9 of 9	NP_057457.1
	WWOX	NM_001291997.2		c.*127G>T		3_prime_UTR	Exon 8 of 8	NP_001278926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WWOX	ENST00000402655.6	TSL:1	c.725G>T	p.Ser242Ile	missense	Exon 5 of 5	ENSP00000384238.2
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.*127G>T		3_prime_UTR	Exon 9 of 9	ENSP00000457230.1
WWOX	ENST00000406884.6	TSL:1	c.*127G>T		3_prime_UTR	Exon 6 of 6	ENSP00000384495.2

Frequencies

GnomAD3 genomes

AF:

0.459

AC:

69715

AN:

151992

Hom.:

17157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.536

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.563

Gnomad OTH

AF:

0.480

GnomAD2 exomes

AF:

0.436

AC:

64037

AN:

146858

AF XY:

0.442

show subpopulations

Gnomad AFR exome

AF:

0.342

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.532

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.569

Gnomad OTH exome

AF:

0.485

GnomAD4 exome

AF:

0.532

AC:

739425

AN:

1389038

Hom.:

204174

Cov.:

AF XY:

0.529

AC XY:

362518

AN XY:

685916

show subpopulations

African (AFR)

AF:

0.341

AC:

10798

AN:

31696

American (AMR)

AF:

0.279

AC:

10015

AN:

35834

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

13468

AN:

25208

East Asian (EAS)

AF:

0.141

AC:

5060

AN:

35862

South Asian (SAS)

AF:

0.365

AC:

29117

AN:

79778

European-Finnish (FIN)

AF:

0.540

AC:

19734

AN:

36532

Middle Eastern (MID)

AF:

0.461

AC:

2629

AN:

5700

European-Non Finnish (NFE)

AF:

0.574

AC:

619858

AN:

1080392

Other (OTH)

AF:

0.495

AC:

28746

AN:

58036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

22973

45946

68920

91893

114866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17134

34268

51402

68536

85670

<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:

0.459

AC:

69747

AN:

152110

Hom.:

17163

Cov.:

AF XY:

0.450

AC XY:

33467

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.345

AC:

14337

AN:

41502

American (AMR)

AF:

0.358

AC:

5477

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.536

AC:

1860

AN:

3470

East Asian (EAS)

AF:

0.136

AC:

699

AN:

5154

South Asian (SAS)

AF:

0.343

AC:

1651

AN:

4820

European-Finnish (FIN)

AF:

0.545

AC:

5769

AN:

10578

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.563

AC:

38275

AN:

67976

Other (OTH)

AF:

0.474

AC:

1001

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1849

3699

5548

7398

9247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.525

Hom.:

92425

Bravo

AF:

0.442

TwinsUK

AF:

0.567

AC:

2103

ALSPAC

AF:

0.574

AC:

2214

ExAC

AF:

0.366

AC:

33799

Asia WGS

AF:

0.242

AC:

842

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.5

(source)

DANN

Benign

0.78

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.19

MetaRNN

Benign

0.00017

MetaSVM

Benign

-0.92

PhyloP100

2.9

PROVEAN

Benign

-0.14

REVEL

Benign

0.092

Sift

Benign

0.44

Sift4G

Benign

0.67

Polyphen

0.92

Vest4

0.20

ClinPred

0.020

GERP RS

1.4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over