rs377442022

Variant names:

• chr16-78115069-C-A
• rs377442022
• NM_016373.4:c.324C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78115069-C-A
• chr16-78115069-C-G
• chr16-78115069-C-T

Variant summary

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

The NM_016373.4(WWOX):​c.324C>A​(p.Asp108Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D108N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.317
• 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.324C>A	p.Asp108Glu	missense_variant	Exon 4 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_130791.5	c.324C>A	p.Asp108Glu	missense_variant	Exon 4 of 6		NP_570607.1
WWOX	NR_120436.3	n.563C>A		non_coding_transcript_exon_variant	Exon 4 of 6
WWOX	NM_001291997.2	c.-16C>A		5_prime_UTR_variant	Exon 3 of 8		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.324C>A	p.Asp108Glu	missense_variant	Exon 4 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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"). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 108 of the WWOX protein (p.Asp108Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	8.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;M
PhyloP100		-0.32
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D;T;D;D
Sift4G	Uncertain	0.015	D;D;D;D;T;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.79
MutPred		0.23		Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);
MVP		0.78
ClinPred		0.99	D
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.56

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: rs377442022; hg19: chr16-78148966;