16-79021201-A-G

Variant names:

• chr16-79021201-A-G
• rs2550716
• NM_016373.4:c.1057-190407A>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.1057-190407A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 152,182 control chromosomes in the GnomAD database, including 46,460 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 0.78 (46460 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 1 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 (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-190407A>G		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-190407A>G		intron_variant	Intron 7 of 7		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.1057-190407A>G		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117938 AN: 152064 Hom.: 46400 Cov.: 33

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.776 AC: 118056 AN: 152182 Hom.: 46460 Cov.: 33 AF XY: 0.774 AC XY: 57556 AN XY: 74390

African (AFR) AF: 0.887 AC: 36847 AN: 41542

American (AMR) AF: 0.813 AC: 12434 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2492 AN: 3468

East Asian (EAS) AF: 0.955 AC: 4932 AN: 5166

South Asian (SAS) AF: 0.762 AC: 3670 AN: 4818

European-Finnish (FIN) AF: 0.674 AC: 7127 AN: 10568

Middle Eastern (MID) AF: 0.688 AC: 201 AN: 292

European-Non Finnish (NFE) AF: 0.708 AC: 48135 AN: 68018

Other (OTH) AF: 0.775 AC: 1636 AN: 2112

Alfa AF: 0.661 Hom.: 2063

Bravo AF: 0.794

Asia WGS AF: 0.861 AC: 2994 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.58
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: rs2550716; hg19: chr16-79055098;