chr16-78843521-C-A

Variant names:

• chr16-78843521-C-A
• rs4888865
• NM_016373.4:c.1057-368087C>A

Variant summary

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

The NM_016373.4(WWOX):​c.1057-368087C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 149,340 control chromosomes in the GnomAD database, including 42,136 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 0.73 (42136 hom., cov: 30)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.791 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.1057-368087C>A		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-368087C>A		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.1057-368087C>A		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-368087C>A		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-368087C>A		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.732 AC: 109278 AN: 149220 Hom.: 42115 Cov.: 30

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.857

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.757

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

GnomAD4 genome AF: 0.732 AC: 109344 AN: 149340 Hom.: 42136 Cov.: 30 AF XY: 0.732 AC XY: 53269 AN XY: 72810

African (AFR) AF: 0.628 AC: 25854 AN: 41188

American (AMR) AF: 0.756 AC: 11268 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2844 AN: 3404

East Asian (EAS) AF: 0.481 AC: 2442 AN: 5074

South Asian (SAS) AF: 0.706 AC: 3193 AN: 4520

European-Finnish (FIN) AF: 0.793 AC: 8089 AN: 10204

Middle Eastern (MID) AF: 0.864 AC: 247 AN: 286

European-Non Finnish (NFE) AF: 0.796 AC: 53181 AN: 66784

Other (OTH) AF: 0.750 AC: 1551 AN: 2068

Alfa AF: 0.755 Hom.: 57364

Asia WGS AF: 0.603 AC: 2082 AN: 3446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.46
DANN	Benign	0.37
PhyloP100		0.32
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: rs4888865; hg19: chr16-78877418;