16-78164216-G-T

Position:

• chr16-78164216-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016373.4(WWOX):​c.443G>T​(p.Gly148Val) 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. 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. G148A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.443G>T	p.Gly148Val	missense_variant	5/9	ENST00000566780.6
WWOX	NM_001291997.2	c.104G>T	p.Gly35Val	missense_variant	4/8
WWOX	NM_130791.5	c.443G>T	p.Gly148Val	missense_variant	5/6
WWOX	NR_120436.3	n.682G>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.443G>T	p.Gly148Val	missense_variant	5/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.3	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.0	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.95
MutPred		0.86		Gain of MoRF binding (P = 0.1015);Gain of MoRF binding (P = 0.1015);Gain of MoRF binding (P = 0.1015);Gain of MoRF binding (P = 0.1015);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.86

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: rs372660669; hg19: chr16-78198113;