rs748074874

Variant names:

• chr16-78432674-G-A
• rs748074874
• NM_016373.4:c.978G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78432674-G-A
• chr16-78432674-G-C
• chr16-78432674-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016373.4(WWOX):​c.978G>A​(p.Met326Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M326T) 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: 9.60
• Publications: 0 publications found

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]

WWOX Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 12

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.978G>A	p.Met326Ile	missense_variant	Exon 8 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.639G>A	p.Met213Ile	missense_variant	Exon 7 of 8		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.978G>A	p.Met326Ile	missense_variant	Exon 8 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.43	N;N;.
PhyloP100		9.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.075	T;T;.
Sift4G	Benign	0.30	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.85
MutPred		0.51		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.70
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.38
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

Other links and lift over

dbSNP: rs748074874; hg19: chr16-78466571; COSMIC: COSV68349872; COSMIC: COSV68349872;