rs3764341

Variant names:

• chr16-78432584-C-G
• rs3764341
• NM_016373.4:c.888C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-78432584-C-G
• chr16-78432584-C-A
• chr16-78432584-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_016373.4(WWOX):​c.888C>G​(p.Ser296Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,614,200 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: WWOX NM_016373.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.48
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.07).
• BP6: Variant 16-78432584-C-G is Benign according to our data. Variant chr16-78432584-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000637 (97/152308) while in subpopulation EAS AF = 0.0139 (72/5180). AF 95% confidence interval is 0.0113. There are 3 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.888C>G	p.Ser296Ser	synonymous	Exon 8 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.549C>G	p.Ser183Ser	synonymous	Exon 7 of 8	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.888C>G	p.Ser296Ser	synonymous	Exon 8 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.888C>G	p.Ser296Ser	synonymous	Exon 8 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.409+317430C>G		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00127 AC: 318 AN: 249580 AF XY: 0.00111

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000466 AC: 681 AN: 1461892 Hom.: 6 Cov.: 32 AF XY: 0.000446 AC XY: 324 AN XY: 727248

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0148 AC: 588 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.000844 AC: 51 AN: 60396

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74460

African (AFR) AF: 0.000409 AC: 17 AN: 41570

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000967

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive spinocerebellar ataxia 12 (1)
-	-	1	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	Developmental and epileptic encephalopathy, 28 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.1
DANN	Benign	0.65
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3764341; hg19: chr16-78466481;