16-78958645-A-G

Variant names:

• chr16-78958645-A-G
• rs10871358
• NM_016373.4:c.1057-252963A>G

Variant summary

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

The NM_016373.4(WWOX):​c.1057-252963A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 152,090 control chromosomes in the GnomAD database, including 22,170 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 0.53 (22170 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 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.1057-252963A>G		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-252963A>G		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.1057-252963A>G		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-252963A>G		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-252963A>G		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80710 AN: 151972 Hom.: 22163 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.531 AC: 80763 AN: 152090 Hom.: 22170 Cov.: 32 AF XY: 0.537 AC XY: 39941 AN XY: 74318

African (AFR) AF: 0.450 AC: 18663 AN: 41490

American (AMR) AF: 0.595 AC: 9092 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2442 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4702 AN: 5166

South Asian (SAS) AF: 0.668 AC: 3217 AN: 4816

European-Finnish (FIN) AF: 0.517 AC: 5467 AN: 10568

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35365 AN: 67982

Other (OTH) AF: 0.563 AC: 1191 AN: 2114

Alfa AF: 0.529 Hom.: 61262

Bravo AF: 0.535

Asia WGS AF: 0.758 AC: 2631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.39
PhyloP100		1.0
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: rs10871358; hg19: chr16-78992542;