16-78171169-C-T

Variant names:

• chr16-78171169-C-T
• rs7201414
• NM_016373.4:c.516+6880C>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.516+6880C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,126 control chromosomes in the GnomAD database, including 1,857 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 0.14 (1857 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 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.516+6880C>T		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.177+6880C>T		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.516+6880C>T		intron	N/A	NP_570607.1	Q9NZC7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.516+6880C>T		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.516+6880C>T		intron	N/A	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.409+56015C>T		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21677 AN: 152008 Hom.: 1857 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.144

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

GnomAD4 genome AF: 0.142 AC: 21675 AN: 152126 Hom.: 1857 Cov.: 32 AF XY: 0.141 AC XY: 10492 AN XY: 74376

African (AFR) AF: 0.0402 AC: 1671 AN: 41532

American (AMR) AF: 0.147 AC: 2252 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 642 AN: 3468

East Asian (EAS) AF: 0.223 AC: 1153 AN: 5166

South Asian (SAS) AF: 0.0911 AC: 438 AN: 4806

European-Finnish (FIN) AF: 0.172 AC: 1818 AN: 10572

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13131 AN: 67984

Other (OTH) AF: 0.143 AC: 301 AN: 2110

Alfa AF: 0.101 Hom.: 176

Bravo AF: 0.138

Asia WGS AF: 0.145 AC: 503 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.81
PhyloP100		0.30
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: rs7201414; hg19: chr16-78205066;