Genetic Variant NM_016373.4:c.324C>G (chr16-78115069-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016373.4(WWOX):c.324C>G(p.Asp108Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D108N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.317

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_130791.5 link	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 6		NP_570607.1	Q9NZC7-3
WWOX	NR_120436.3 link	n.563C>G		non_coding_transcript_exon_variant	Exon 4 of 6
WWOX	NM_001291997.2 link	c.-16C>G		5_prime_UTR_variant	Exon 3 of 8		NP_001278926.1	Q9NZC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249576

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000270

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.17

CADD

Benign

9.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;.;.;T;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.5

M;M;M;.;M;M

PhyloP100

-0.32

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0050

D;D;D;T;D;D

Sift4G

Uncertain

0.015

D;D;D;D;T;D

Polyphen

1.0

D;D;D;.;D;.

Vest4

0.79

MutPred

0.23

Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);

MVP

0.78

ClinPred

0.98

GERP RS

-3.9

Varity_R

0.41

gMVP

0.56

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over