16-78099879-A-T

Variant names:

• chr16-78099879-A-T
• rs766309882
• NM_016373.4:c.101A>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.101A>T​(p.Tyr34Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,413,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y34C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.37300208).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. 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.101A>T	p.Tyr34Phe	missense	Exon 1 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_130791.5		c.101A>T	p.Tyr34Phe	missense	Exon 1 of 6	NP_570607.1	Q9NZC7-3
	WWOX	NM_001291997.2		c.-174A>T		5_prime_UTR	Exon 1 of 8	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.101A>T	p.Tyr34Phe	missense	Exon 1 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.101A>T	p.Tyr34Phe	missense	Exon 1 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.101A>T	p.Tyr34Phe	missense	Exon 1 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000118 AC: 2 AN: 168950 AF XY: 0.0000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1413216 Hom.: 0 Cov.: 31 AF XY: 0.00000429 AC XY: 3 AN XY: 698726

African (AFR) AF: 0.00 AC: 0 AN: 31990

American (AMR) AF: 0.00 AC: 0 AN: 37446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36568

South Asian (SAS) AF: 0.0000376 AC: 3 AN: 79794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088100

Other (OTH) AF: 0.00 AC: 0 AN: 58536

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000858 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.72
Sift	Benign	0.14	T
Sift4G	Uncertain	0.042	D
Polyphen		0.84	P
Vest4		0.31
MutPred		0.70		Loss of phosphorylation at Y34 (P = 0.0243)
MVP		0.78
ClinPred		0.81	D
GERP RS		3.8
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766309882; hg19: chr16-78133776;