rs776553279

Variant names:

• chr16-78099830-C-A
• rs776553279
• NM_016373.4:c.52C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78099830-C-A
• chr16-78099830-C-G
• chr16-78099830-C-T

Variant summary

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

The NM_001291997.2(WWOX):​c.-223C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WWOX NM_001291997.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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=0.37453458).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291997.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.52C>A	p.Leu18Met	missense	Exon 1 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.-223C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001278926.1
	WWOX	NM_130791.5		c.52C>A	p.Leu18Met	missense	Exon 1 of 6	NP_570607.1	Q9NZC7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.52C>A	p.Leu18Met	missense	Exon 1 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.52C>A	p.Leu18Met	missense	Exon 1 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.52C>A	p.Leu18Met	missense	Exon 1 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1429580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708418

African (AFR) AF: 0.00 AC: 0 AN: 32452

American (AMR) AF: 0.00 AC: 0 AN: 39956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25450

East Asian (EAS) AF: 0.00 AC: 0 AN: 37684

South Asian (SAS) AF: 0.00 AC: 0 AN: 81224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097018

Other (OTH) AF: 0.00 AC: 0 AN: 59158

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.71		Loss of catalytic residue at L18 (P = 0.0051)
MVP		0.91
ClinPred		0.97	D
GERP RS		3.0
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.36

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: rs776553279; hg19: chr16-78133727;