16-78099789-T-G

Variant names:

• chr16-78099789-T-G
• NM_016373.4:c.11T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016373.4(WWOX):​c.11T>G​(p.Leu4Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000711 in 1,406,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.16
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.11T>G	p.Leu4Arg	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.11T>G	p.Leu4Arg	missense_variant	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406234 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695308

African (AFR) AF: 0.00 AC: 0 AN: 31450

American (AMR) AF: 0.00 AC: 0 AN: 35630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

East Asian (EAS) AF: 0.00 AC: 0 AN: 36206

South Asian (SAS) AF: 0.00 AC: 0 AN: 78994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5256

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085792

Other (OTH) AF: 0.00 AC: 0 AN: 58242

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11T>G (p.L4R) alteration is located in exon 1 (coding exon 1) of the WWOX gene. This alteration results from a T to G substitution at nucleotide position 11, causing the leucine (L) at amino acid position 4 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 18, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.;.;T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.55	N;.;N;N;.;N;N;N
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;.;N;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D;D;.
Vest4		0.83
MutPred		0.31		Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);Gain of disorder (P = 0.0233);
MVP		0.96
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.0062	Neutral
Varity_R		0.70
gMVP		0.34
Mutation Taster		=46/54	disease causing

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

hg19: chr16-78133686;