NM_016373.4:c.1056+176157C>A

Variant names:

• chr16-78608909-C-A
• rs2548879
• NM_016373.4:c.1056+176157C>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.1056+176157C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,974 control chromosomes in the GnomAD database, including 17,516 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 0.45 (17516 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• 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

ENSG00000288821 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.582 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1056+176157C>A		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.717+176157C>A		intron	N/A	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1056+176157C>A		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.1057-82333C>A		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.409+493755C>A		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68014 AN: 151858 Hom.: 17510 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.448 AC: 68037 AN: 151974 Hom.: 17516 Cov.: 32 AF XY: 0.449 AC XY: 33329 AN XY: 74260

African (AFR) AF: 0.172 AC: 7154 AN: 41478

American (AMR) AF: 0.593 AC: 9052 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2035 AN: 3472

East Asian (EAS) AF: 0.537 AC: 2766 AN: 5148

South Asian (SAS) AF: 0.472 AC: 2267 AN: 4802

European-Finnish (FIN) AF: 0.501 AC: 5275 AN: 10536

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37697 AN: 67950

Other (OTH) AF: 0.497 AC: 1049 AN: 2110

Alfa AF: 0.497 Hom.: 11607

Bravo AF: 0.446

Asia WGS AF: 0.463 AC: 1609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.2
DANN	Benign	0.59
PhyloP100		0.087
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: rs2548879; hg19: chr16-78642806;