rs4888846

Variant names:

• chr16-78771866-A-T
• rs4888846
• NM_016373.4:c.1056+339114A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016373.4(WWOX):​c.1056+339114A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,840 control chromosomes in the GnomAD database, including 7,794 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7794 hom., cov: 31)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.43
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1056+339114A>T		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.717+339114A>T		intron	N/A	NP_001278926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1056+339114A>T		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.*16-8549A>T		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.410-439742A>T		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47105 AN: 151730 Hom.: 7779 Cov.: 31

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.297

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.311 AC: 47147 AN: 151840 Hom.: 7794 Cov.: 31 AF XY: 0.304 AC XY: 22597 AN XY: 74242

African (AFR) AF: 0.355 AC: 14677 AN: 41330

American (AMR) AF: 0.233 AC: 3554 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1230 AN: 3468

East Asian (EAS) AF: 0.0879 AC: 455 AN: 5178

South Asian (SAS) AF: 0.376 AC: 1811 AN: 4816

European-Finnish (FIN) AF: 0.236 AC: 2479 AN: 10526

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.322 AC: 21895 AN: 67952

Other (OTH) AF: 0.305 AC: 644 AN: 2110

Alfa AF: 0.323 Hom.: 760

Bravo AF: 0.304

Asia WGS AF: 0.257 AC: 890 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0060
DANN	Benign	0.18
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs4888846; hg19: chr16-78805763;