rs3764340

chr16-78432540-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):c.844C>G(p.Pro282Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,098 control chromosomes in the GnomAD database, including 3,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P282L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (476 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2915 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044485033).
• BP6: Variant 16-78432540-C-G is Benign according to our data. Variant chr16-78432540-C-G is described in ClinVar as [Benign]. Clinvar id is 260745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.844C>G	p.Pro282Ala	missense_variant	8/9	ENST00000566780.6
WWOX	NM_001291997.2	c.505C>G	p.Pro169Ala	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.844C>G	p.Pro282Ala	missense_variant	8/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11184 AN: 152100 Hom.: 477 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0916

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0686

GnomAD3 exomes AF: 0.0711 AC: 17732 AN: 249482 Hom.: 688 AF XY: 0.0707 AC XY: 9568 AN XY: 135376

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.0797

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.0867

Gnomad SAS exome AF: 0.0893

Gnomad FIN exome AF: 0.0560

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0710

GnomAD4 exome AF: 0.0595 AC: 87031 AN: 1461880 Hom.: 2915 Cov.: 32 AF XY: 0.0601 AC XY: 43702 AN XY: 727242

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.0797

Gnomad4 ASJ exome AF: 0.0987

Gnomad4 EAS exome AF: 0.0814

Gnomad4 SAS exome AF: 0.0875

Gnomad4 FIN exome AF: 0.0610

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0645

GnomAD4 genome AF: 0.0736 AC: 11203 AN: 152218 Hom.: 476 Cov.: 32 AF XY: 0.0739 AC XY: 5500 AN XY: 74410

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.0800

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0916

Gnomad4 SAS AF: 0.0918

Gnomad4 FIN AF: 0.0540

Gnomad4 NFE AF: 0.0575

Gnomad4 OTH AF: 0.0683

Alfa AF: 0.0611 Hom.: 241

Bravo AF: 0.0721

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.0865 AC: 340

ESP6500EA AF: 0.0592 AC: 491

ExAC AF: 0.0743 AC: 8977

Asia WGS AF: 0.0890 AC: 312 AN: 3478

EpiCase AF: 0.0547

EpiControl AF: 0.0549

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive spinocerebellar ataxia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.2e-9	P;P;P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.0	D;D;.
Sift	Benign	0.066	T;T;.
Sift4G	Benign	0.54	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.42
ClinPred		0.045	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.78

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: rs3764340; hg19: chr16-78466437; COSMIC: COSV68347728;