16-78970586-A-C

Variant names:

• chr16-78970586-A-C
• rs1467067
• NM_016373.4:c.1057-241022A>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.1057-241022A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,176 control chromosomes in the GnomAD database, including 4,364 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 0.22 (4364 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 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.1057-241022A>C		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.718-241022A>C		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.1057-241022A>C		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000402655.6	TSL:1	c.410-241022A>C		intron	N/A	ENSP00000384238.2	Q9NZC7-6
	WWOX	ENST00000406884.6	TSL:1	c.517-241022A>C		intron	N/A	ENSP00000384495.2	Q9NZC7-5

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34167 AN: 152058 Hom.: 4367 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.224 AC: 34163 AN: 152176 Hom.: 4364 Cov.: 32 AF XY: 0.218 AC XY: 16242 AN XY: 74382

African (AFR) AF: 0.145 AC: 6042 AN: 41546

American (AMR) AF: 0.188 AC: 2872 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 691 AN: 3466

East Asian (EAS) AF: 0.0133 AC: 69 AN: 5182

South Asian (SAS) AF: 0.176 AC: 848 AN: 4818

European-Finnish (FIN) AF: 0.237 AC: 2501 AN: 10572

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.300 AC: 20421 AN: 67986

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.253 Hom.: 9249

Bravo AF: 0.216

Asia WGS AF: 0.102 AC: 353 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	3.8
DANN	Benign	0.66
PhyloP100		-0.0040
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: rs1467067; hg19: chr16-79004483;