16-79010752-G-T

Variant names:

• chr16-79010752-G-T
• rs2550731
• NM_016373.4:c.1057-200856G>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.1057-200856G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 148,854 control chromosomes in the GnomAD database, including 11,097 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 0.37 (11097 hom., cov: 24)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.937
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-200856G>T		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-200856G>T		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.1057-200856G>T		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 55386 AN: 148740 Hom.: 11076 Cov.: 24

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.388

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

GnomAD4 genome AF: 0.372 AC: 55444 AN: 148854 Hom.: 11097 Cov.: 24 AF XY: 0.378 AC XY: 27354 AN XY: 72402

African (AFR) AF: 0.287 AC: 11565 AN: 40296

American (AMR) AF: 0.497 AC: 7417 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1330 AN: 3444

East Asian (EAS) AF: 0.818 AC: 4016 AN: 4910

South Asian (SAS) AF: 0.526 AC: 2429 AN: 4622

European-Finnish (FIN) AF: 0.316 AC: 3198 AN: 10106

Middle Eastern (MID) AF: 0.326 AC: 94 AN: 288

European-Non Finnish (NFE) AF: 0.358 AC: 24100 AN: 67320

Other (OTH) AF: 0.396 AC: 811 AN: 2048

Alfa AF: 0.369 Hom.: 21144

Bravo AF: 0.382

Asia WGS AF: 0.641 AC: 2224 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.24
DANN	Benign	0.56
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2550731; hg19: chr16-79044649;