NM_016373.4:c.1057-261369C>T

Variant names:

• chr16-78950239-C-T
• rs1995549
• NM_016373.4:c.1057-261369C>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.1057-261369C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 151,978 control chromosomes in the GnomAD database, including 28,904 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 0.61 (28904 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.378
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 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.1057-261369C>T		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-261369C>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.1057-261369C>T		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-261369C>T		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-261369C>T		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92898 AN: 151858 Hom.: 28876 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.637

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

GnomAD4 genome AF: 0.612 AC: 92977 AN: 151978 Hom.: 28904 Cov.: 32 AF XY: 0.605 AC XY: 44970 AN XY: 74284

African (AFR) AF: 0.686 AC: 28457 AN: 41462

American (AMR) AF: 0.602 AC: 9192 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2536 AN: 3472

East Asian (EAS) AF: 0.541 AC: 2793 AN: 5158

South Asian (SAS) AF: 0.606 AC: 2919 AN: 4818

European-Finnish (FIN) AF: 0.473 AC: 4988 AN: 10544

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39939 AN: 67948

Other (OTH) AF: 0.639 AC: 1348 AN: 2108

Alfa AF: 0.605 Hom.: 87779

Bravo AF: 0.627

Asia WGS AF: 0.613 AC: 2134 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.5
DANN	Benign	0.82
PhyloP100		0.38
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: rs1995549; hg19: chr16-78984136;