ENST00000402655.6:c.523C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_StrongBP6_Very_Strong

The ENST00000402655.6(WWOX):​c.523C>T​(p.Arg175*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,068 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. R175R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

WWOX
ENST00000402655.6 stop_gained

Scores

2
13

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.15

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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.441 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
BP6
Variant 16-79211721-C-T is Benign according to our data. Variant chr16-79211721-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 415951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WWOXNM_016373.4 linkc.1170C>T p.Ser390Ser synonymous_variant Exon 9 of 9 ENST00000566780.6 NP_057457.1 Q9NZC7-1A0A411HBC7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WWOXENST00000566780.6 linkc.1170C>T p.Ser390Ser synonymous_variant Exon 9 of 9 1 NM_016373.4 ENSP00000457230.1 Q9NZC7-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000842
AC:
21
AN:
249528
AF XY:
0.0000960
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.0000618
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000513
AC:
75
AN:
1461880
Hom.:
0
Cov.:
88
AF XY:
0.0000646
AC XY:
47
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.000329
AC:
11
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.000128
AC:
11
AN:
86258
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000369
AC:
41
AN:
1112006
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.000125
AC:
19
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74342
show subpopulations
African (AFR)
AF:
0.000362
AC:
15
AN:
41460
American (AMR)
AF:
0.000131
AC:
2
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000540
Hom.:
0
Bravo
AF:
0.000196
ESP6500AA
AF:
0.000750
AC:
3
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000744
AC:
9
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Oct 22, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
0.18
DANN
Benign
0.92
DEOGEN2
Benign
0.014
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.39
T
MetaRNN
Benign
0.040
T
MetaSVM
Benign
-1.0
T
PhyloP100
-3.1
PROVEAN
Benign
0.010
N
REVEL
Benign
0.016
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.14
MVP
0.41
ClinPred
0.020
T
GERP RS
-6.8

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

Other links and lift over

dbSNP: rs372635911; hg19: chr16-79245618; COSMIC: COSV68364927; COSMIC: COSV68364927; API