rs4600477

Variant names:

• chr16-78963966-G-A
• rs4600477
• NM_016373.4:c.1057-247642G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78963966-G-A
• chr16-78963966-G-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.1057-247642G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,018 control chromosomes in the GnomAD database, including 32,203 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 0.64 (32203 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• 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=-1.06).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-247642G>A		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-247642G>A		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.1057-247642G>A		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97691 AN: 151900 Hom.: 32172 Cov.: 32

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.639

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

GnomAD4 genome AF: 0.643 AC: 97775 AN: 152018 Hom.: 32203 Cov.: 32 AF XY: 0.638 AC XY: 47411 AN XY: 74300

African (AFR) AF: 0.791 AC: 32805 AN: 41482

American (AMR) AF: 0.581 AC: 8877 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1825 AN: 3470

East Asian (EAS) AF: 0.522 AC: 2691 AN: 5152

South Asian (SAS) AF: 0.602 AC: 2905 AN: 4822

European-Finnish (FIN) AF: 0.584 AC: 6152 AN: 10540

Middle Eastern (MID) AF: 0.603 AC: 176 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 40444 AN: 67968

Other (OTH) AF: 0.636 AC: 1345 AN: 2114

Alfa AF: 0.522 Hom.: 1565

Bravo AF: 0.647

Asia WGS AF: 0.590 AC: 2056 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.19
DANN	Benign	0.11
PhyloP100		-1.6
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: rs4600477; hg19: chr16-78997863;