16-79211594-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016373.4(WWOX):c.1057-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,614,050 control chromosomes in the GnomAD database, including 1,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 120 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1565 hom. )

Consequence

WWOX
NM_016373.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.909

Publications

3 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:

ENSG00000261722 (HGNC:):

ENSG00000261722 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:

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=-0.8).

BP6

Variant 16-79211594-T-C is Benign according to our data. Variant chr16-79211594-T-C is described in ClinVar as Benign. ClinVar VariationId is 260736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0372 (5658/152262) while in subpopulation NFE AF = 0.0474 (3226/68028). AF 95% confidence interval is 0.0461. There are 120 homozygotes in GnomAd4. There are 2802 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 120 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1057-14T>C		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-14T>C		intron	N/A	NP_001278926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-14T>C	intron	N/A	ENSP00000457230.1
WWOX	ENST00000402655.6	TSL:1	c.410-14T>C	intron	N/A	ENSP00000384238.2
WWOX	ENST00000406884.6	TSL:1	c.517-14T>C	intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes

AF:

0.0372

AC:

5656

AN:

152144

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.0260

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.0641

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0474

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0373

AC:

9248

AN:

248250

AF XY:

0.0382

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.0333

Gnomad EAS exome

AF:

0.0237

Gnomad FIN exome

AF:

0.0621

Gnomad NFE exome

AF:

0.0455

Gnomad OTH exome

AF:

0.0327

GnomAD4 exome

AF:

0.0440

AC:

64297

AN:

1461788

Hom.:

1565

Cov.:

AF XY:

0.0442

AC XY:

32151

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0198

AC:

662

AN:

33466

American (AMR)

AF:

0.0156

AC:

697

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0327

AC:

855

AN:

26134

East Asian (EAS)

AF:

0.0346

AC:

1375

AN:

39692

South Asian (SAS)

AF:

0.0349

AC:

3008

AN:

86246

European-Finnish (FIN)

AF:

0.0612

AC:

3268

AN:

53418

Middle Eastern (MID)

AF:

0.0227

AC:

131

AN:

5768

European-Non Finnish (NFE)

AF:

0.0465

AC:

51756

AN:

1111970

Other (OTH)

AF:

0.0421

AC:

2545

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3708

7415

11123

14830

18538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1868

3736

5604

7472

9340

<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:

0.0372

AC:

5658

AN:

152262

Hom.:

120

Cov.:

AF XY:

0.0376

AC XY:

2802

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0218

AC:

907

AN:

41562

American (AMR)

AF:

0.0232

AC:

355

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3466

East Asian (EAS)

AF:

0.0263

AC:

136

AN:

5174

South Asian (SAS)

AF:

0.0351

AC:

169

AN:

4818

European-Finnish (FIN)

AF:

0.0641

AC:

679

AN:

10594

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0474

AC:

3226

AN:

68028

Other (OTH)

AF:

0.0298

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

289

578

866

1155

1444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0334

Hom.:

Bravo

AF:

0.0328

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy, 28

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal recessive spinocerebellar ataxia 12

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.1

(source)

DANN

Benign

0.73

PhyloP100

0.91

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over