16-78154006-A-G

Variant names:

• chr16-78154006-A-G
• rs12716850
• NM_016373.4:c.410-10177A>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.410-10177A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 151,728 control chromosomes in the GnomAD database, including 24,957 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 (24957 hom., cov: 30)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.67
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.410-10177A>G		intron_variant	Intron 4 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.71-10177A>G		intron_variant	Intron 3 of 7		NP_001278926.1
WWOX	NM_130791.5	c.410-10177A>G		intron_variant	Intron 4 of 5		NP_570607.1
WWOX	NR_120436.3	n.649-10177A>G		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.410-10177A>G		intron_variant	Intron 4 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86540 AN: 151610 Hom.: 24936 Cov.: 30

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.571 AC: 86609 AN: 151728 Hom.: 24957 Cov.: 30 AF XY: 0.567 AC XY: 42056 AN XY: 74152

African (AFR) AF: 0.654 AC: 27022 AN: 41346

American (AMR) AF: 0.537 AC: 8186 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1855 AN: 3466

East Asian (EAS) AF: 0.511 AC: 2617 AN: 5124

South Asian (SAS) AF: 0.499 AC: 2394 AN: 4794

European-Finnish (FIN) AF: 0.545 AC: 5738 AN: 10532

Middle Eastern (MID) AF: 0.459 AC: 133 AN: 290

European-Non Finnish (NFE) AF: 0.545 AC: 36993 AN: 67922

Other (OTH) AF: 0.552 AC: 1162 AN: 2106

Alfa AF: 0.551 Hom.: 61707

Bravo AF: 0.574

Asia WGS AF: 0.502 AC: 1750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0070
DANN	Benign	0.35
PhyloP100		-3.7
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: rs12716850; hg19: chr16-78187903;