16-78099830-C-G

Position:

• chr16-78099830-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016373.4(WWOX):​c.52C>G​(p.Leu18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,429,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4	c.52C>G	p.Leu18Val	missense_variant	1/9	ENST00000566780.6	NP_057457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.52C>G	p.Leu18Val	missense_variant	1/9	1	NM_016373.4	ENSP00000457230	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000304 AC: 6 AN: 197122 Hom.: 0 AF XY: 0.0000188 AC XY: 2 AN XY: 106416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000140

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: 0.0000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 40 AN: 1429580 Hom.: 0 Cov.: 31 AF XY: 0.0000212 AC XY: 15 AN XY: 708418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000125

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: 0.0000310

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000835 AC: 1

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

Oct 22, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the WWOX protein (p.Leu18Val). This variant is present in population databases (rs776553279, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1037991). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;.;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	M;.;M;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;.;D;N;D;D;D;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;.;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;B;D;.
Vest4		0.43
MutPred		0.75		Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);Loss of catalytic residue at L18 (P = 0.042);
MVP		0.97
ClinPred		0.89	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.80
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776553279; hg19: chr16-78133727;