16-78432639-G-T

Position:

• chr16-78432639-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016373.4(WWOX):​c.943G>T​(p.Gly315Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4	c.943G>T	p.Gly315Trp	missense_variant	8/9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.604G>T	p.Gly202Trp	missense_variant	7/8		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.943G>T	p.Gly315Trp	missense_variant	8/9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with WWOX-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 315 of the WWOX protein (p.Gly315Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Pathogenic	3.5	M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D;D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.59		Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);.;
MVP		0.97
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.88

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

Other links and lift over

dbSNP: rs768172617; hg19: chr16-78466536;