16-78099779-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_016373.4(WWOX):c.1A>C(p.Met1?) variant causes a start lost 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WWOX NM_016373.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.37

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_016373.4 (WWOX) was described as [Pathogenic] in ClinVar as 1898392
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-78099779-A-C is Pathogenic according to our data. Variant chr16-78099779-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1979930.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1A>C	p.Met1?	start_lost	1/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1A>C	p.Met1?	start_lost	1/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 07, 2022

This sequence change affects the initiator methionine of the WWOX mRNA. The next in-frame methionine is located at codon 114. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. This variant disrupts a region of the WWOX protein in which other variant(s) (p.Pro47Thr) have been determined to be pathogenic (PMID: 24369382). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Benign	0.94
DEOGEN2	Benign	0.14	T;T;.;.;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-0.76	N;.;N;N;N;N;N;N
Sift	Benign	0.30	T;.;T;T;T;D;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.73	P;.;B;P;.;B;P;.
Vest4		0.77
MutPred		0.99		Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);
MVP		0.85
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-78133676;