chr16-78099785-G-T

Variant names:

• chr16-78099785-G-T
• rs1336300148
• NM_016373.4:c.7G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016373.4(WWOX):​c.7G>T​(p.Ala3Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,403,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.94
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36090103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 9	ENST00000566780.6	NP_057457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000185 AC: 3 AN: 162322 AF XY: 0.0000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000853

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1403360 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693548

African (AFR) AF: 0.00 AC: 0 AN: 31392

American (AMR) AF: 0.0000568 AC: 2 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24860

East Asian (EAS) AF: 0.00 AC: 0 AN: 35986

South Asian (SAS) AF: 0.00 AC: 0 AN: 78804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084144

Other (OTH) AF: 0.00 AC: 0 AN: 58104

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the WWOX protein (p.Ala3Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 858524). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Inborn genetic diseases Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>T (p.A3S) alteration is located in exon 1 (coding exon 1) of the WWOX gene. This alteration results from a G to T substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	0.0	N;.;N;N;.;N;N;N
PhyloP100		8.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.42	N;.;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.39	T;.;T;T;T;D;T;T
Sift4G	Benign	0.25	T;T;D;T;T;T;T;T
Polyphen		1.0	D;.;P;D;.;D;D;.
Vest4		0.54
MutPred		0.22		Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);Gain of phosphorylation at A3 (P = 0.0241);
MVP		0.95
ClinPred		0.71	D
GERP RS		5.1
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.22

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: rs1336300148; hg19: chr16-78133682; COSMIC: COSV63437805; COSMIC: COSV63437805;