16-79211739-C-G

Position:

• chr16-79211739-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000402655.6(WWOX):​c.541C>G​(p.Pro181Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P181L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WWOX ENST00000402655.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714

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]

MAF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 9 uncertain in ENST00000402655.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.119511336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1188C>G	p.Thr396=	synonymous_variant	9/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1188C>G	p.Thr396=	synonymous_variant	9/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.0
DANN	Benign	0.82
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.21	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	1.2	N
REVEL	Benign	0.042
Sift	Benign	0.075	T
Sift4G	Benign	0.15	T
Polyphen		0.010	B
Vest4		0.17
MutPred		0.40		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.64
ClinPred		0.070	T
GERP RS		1.3

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: rs923268639; hg19: chr16-79245636;