rs8056446

Variant names:

• chr16-78154599-G-A
• rs8056446
• NM_016373.4:c.410-9584G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78154599-G-A
• chr16-78154599-G-C
• chr16-78154599-G-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.410-9584G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 148,776 control chromosomes in the GnomAD database, including 24,393 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 0.57 (24393 hom., cov: 25)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 8 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.410-9584G>A		intron_variant	Intron 4 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.71-9584G>A		intron_variant	Intron 3 of 7		NP_001278926.1
WWOX	NM_130791.5	c.410-9584G>A		intron_variant	Intron 4 of 5		NP_570607.1
WWOX	NR_120436.3	n.649-9584G>A		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.410-9584G>A		intron_variant	Intron 4 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 85203 AN: 148662 Hom.: 24372 Cov.: 25

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.457

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.573 AC: 85272 AN: 148776 Hom.: 24393 Cov.: 25 AF XY: 0.571 AC XY: 41318 AN XY: 72302

African (AFR) AF: 0.651 AC: 26351 AN: 40482

American (AMR) AF: 0.549 AC: 8051 AN: 14670

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1840 AN: 3464

East Asian (EAS) AF: 0.518 AC: 2536 AN: 4900

South Asian (SAS) AF: 0.505 AC: 2332 AN: 4616

European-Finnish (FIN) AF: 0.562 AC: 5608 AN: 9984

Middle Eastern (MID) AF: 0.465 AC: 131 AN: 282

European-Non Finnish (NFE) AF: 0.545 AC: 36782 AN: 67434

Other (OTH) AF: 0.558 AC: 1142 AN: 2048

Alfa AF: 0.559 Hom.: 12089

Bravo AF: 0.571

Asia WGS AF: 0.502 AC: 1749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.69
PhyloP100		0.12
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: rs8056446; hg19: chr16-78188496;