NM_016373.4:c.107+673T>C

Variant names:

• chr16-78100558-T-C
• rs4887935
• NM_016373.4:c.107+673T>C

Variant summary

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

The NM_016373.4(WWOX):​c.107+673T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,168 control chromosomes in the GnomAD database, including 11,116 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 0.38 (11116 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.618
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.472 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.107+673T>C		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.-168+673T>C		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.107+673T>C		intron	N/A	NP_570607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.107+673T>C		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.107+673T>C		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.107+673T>C		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57582 AN: 152050 Hom.: 11107 Cov.: 33

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.379 AC: 57627 AN: 152168 Hom.: 11116 Cov.: 33 AF XY: 0.381 AC XY: 28321 AN XY: 74406

African (AFR) AF: 0.365 AC: 15144 AN: 41512

American (AMR) AF: 0.444 AC: 6791 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1221 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1906 AN: 5162

South Asian (SAS) AF: 0.489 AC: 2358 AN: 4824

European-Finnish (FIN) AF: 0.349 AC: 3694 AN: 10590

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25073 AN: 67998

Other (OTH) AF: 0.421 AC: 890 AN: 2112

Alfa AF: 0.374 Hom.: 27608

Bravo AF: 0.382

Asia WGS AF: 0.486 AC: 1687 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	4.5
DANN	Benign	0.77
PhyloP100		0.62
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: rs4887935; hg19: chr16-78134455;