rs114755364

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_016373.4(WWOX):c.332C>G(p.Thr111Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000554 in 1,614,186 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T111I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 4 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008024842).

BP6

Variant 16-78115077-C-G is Benign according to our data. Variant chr16-78115077-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383820.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}. Variant chr16-78115077-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00297 (452/152302) while in subpopulation AFR AF= 0.0104 (432/41560). AF 95% confidence interval is 0.00958. There are 1 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
WWOX	NM_016373.4 linkuse as main transcript	c.332C>G	p.Thr111Ser	missense_variant	4/9	ENST00000566780.6
WWOX	NM_130791.5 linkuse as main transcript	c.332C>G	p.Thr111Ser	missense_variant	4/6
WWOX	NM_001291997.2 linkuse as main transcript	c.-8C>G		5_prime_UTR_variant	3/8
WWOX	NR_120436.3 linkuse as main transcript	n.571C>G		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.332C>G	p.Thr111Ser	missense_variant	4/9	1	NM_016373.4	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000713

AC:

178

AN:

249566

Hom.:

AF XY:

0.000487

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000302

AC:

442

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.00297

AC:

452

AN:

152302

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.00354

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000819

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 17, 2019

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.081

T;.;.;T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.014

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

MetaRNN

Benign

0.0080

T;T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.010

N;N;N;.;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

0.53

N;N;N;N;N;N

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0030

B;B;B;.;B;.

Vest4

0.30

MutPred

0.26

Loss of glycosylation at T111 (P = 0.0634);Loss of glycosylation at T111 (P = 0.0634);Loss of glycosylation at T111 (P = 0.0634);Loss of glycosylation at T111 (P = 0.0634);Loss of glycosylation at T111 (P = 0.0634);Loss of glycosylation at T111 (P = 0.0634);

MVP

0.87

ClinPred

0.039

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over