chr16-78099779-A-C

Variant names:

• chr16-78099779-A-C
• NM_016373.4:c.1A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001291997.2(WWOX):​c.-274A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WWOX NM_001291997.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.37
• 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: 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 16-78099779-A-C is Pathogenic according to our data. Variant chr16-78099779-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1979930.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.-274A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001278926.1
	WWOX	NM_130791.5		c.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

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
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.26	D
PhyloP100		8.4
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.46
Sift	Benign	0.30	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.73	P
Vest4		0.77
MutPred		0.99		Gain of stability (P = 0.0265)
MVP		0.85
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.20
Mutation Taster		=12/188	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: chr16-78133676;