NM_016373.4:c.1057-77560A>G

Variant names:

• chr16-79134048-A-G
• rs1424110
• NM_016373.4:c.1057-77560A>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.1057-77560A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 151,954 control chromosomes in the GnomAD database, including 5,207 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 0.25 (5207 hom., cov: 31)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 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.1057-77560A>G		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-77560A>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.1057-77560A>G		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-77560A>G		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-77560A>G		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38328 AN: 151838 Hom.: 5211 Cov.: 31

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.277

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

GnomAD4 genome AF: 0.252 AC: 38340 AN: 151954 Hom.: 5207 Cov.: 31 AF XY: 0.257 AC XY: 19083 AN XY: 74250

African (AFR) AF: 0.163 AC: 6750 AN: 41456

American (AMR) AF: 0.253 AC: 3859 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1062 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1956 AN: 5164

South Asian (SAS) AF: 0.373 AC: 1791 AN: 4804

European-Finnish (FIN) AF: 0.333 AC: 3509 AN: 10534

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18607 AN: 67946

Other (OTH) AF: 0.276 AC: 581 AN: 2104

Alfa AF: 0.209 Hom.: 1563

Bravo AF: 0.241

Asia WGS AF: 0.346 AC: 1200 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.78
PhyloP100		-0.079
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: rs1424110; hg19: chr16-79167945;