rs11645006

Variant names:

• chr16-78119260-A-G
• rs11645006
• NM_016373.4:c.409+4106A>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.409+4106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 152,110 control chromosomes in the GnomAD database, including 10,571 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 (10571 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.409+4106A>G		intron_variant	Intron 4 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.70+4106A>G		intron_variant	Intron 3 of 7		NP_001278926.1
WWOX	NM_130791.5	c.409+4106A>G		intron_variant	Intron 4 of 5		NP_570607.1
WWOX	NR_120436.3	n.648+4106A>G		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.409+4106A>G		intron_variant	Intron 4 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56120 AN: 151992 Hom.: 10552 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.369 AC: 56184 AN: 152110 Hom.: 10571 Cov.: 33 AF XY: 0.366 AC XY: 27243 AN XY: 74368

African (AFR) AF: 0.407 AC: 16887 AN: 41478

American (AMR) AF: 0.336 AC: 5143 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3472

East Asian (EAS) AF: 0.501 AC: 2589 AN: 5168

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4816

European-Finnish (FIN) AF: 0.332 AC: 3514 AN: 10580

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24572 AN: 67988

Other (OTH) AF: 0.336 AC: 708 AN: 2108

Alfa AF: 0.362 Hom.: 27645

Bravo AF: 0.373

Asia WGS AF: 0.337 AC: 1172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.056
DANN	Benign	0.33
PhyloP100		-0.32
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: rs11645006; hg19: chr16-78153157;