chr16-78224913-A-C

Variant names:

• chr16-78224913-A-C
• rs2059238
• NM_016373.4:c.516+60624A>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.516+60624A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.845 in 152,218 control chromosomes in the GnomAD database, including 54,907 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 0.85 (54907 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.957
• Publications: 17 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.516+60624A>C		intron_variant	Intron 5 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.177+60624A>C		intron_variant	Intron 4 of 7		NP_001278926.1
WWOX	NM_130791.5	c.517-53690A>C		intron_variant	Intron 5 of 5		NP_570607.1
WWOX	NR_120436.3	n.756-53690A>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.516+60624A>C		intron_variant	Intron 5 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.845 AC: 128572 AN: 152100 Hom.: 54845 Cov.: 32

Gnomad AFR AF: 0.962

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.854

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

GnomAD4 genome AF: 0.845 AC: 128691 AN: 152218 Hom.: 54907 Cov.: 32 AF XY: 0.843 AC XY: 62695 AN XY: 74414

African (AFR) AF: 0.962 AC: 40000 AN: 41572

American (AMR) AF: 0.883 AC: 13504 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3058 AN: 3472

East Asian (EAS) AF: 0.837 AC: 4341 AN: 5184

South Asian (SAS) AF: 0.786 AC: 3783 AN: 4812

European-Finnish (FIN) AF: 0.715 AC: 7559 AN: 10576

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53647 AN: 67992

Other (OTH) AF: 0.852 AC: 1800 AN: 2112

Alfa AF: 0.818 Hom.: 152980

Bravo AF: 0.864

Asia WGS AF: 0.816 AC: 2839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.69
DANN	Benign	0.35
PhyloP100		-0.96
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: rs2059238; hg19: chr16-78258810;