rs3764340

Variant names:

• chr16-78432540-C-G
• rs3764340
• NM_016373.4:c.844C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-78432540-C-G
• chr16-78432540-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.844C>G​(p.Pro282Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,098 control chromosomes in the GnomAD database, including 3,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P282L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (476 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2915 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.57
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044485033).
• BP6: Variant 16-78432540-C-G is Benign according to our data. Variant chr16-78432540-C-G is described in ClinVar as Benign. ClinVar VariationId is 260745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.844C>G	p.Pro282Ala	missense	Exon 8 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.505C>G	p.Pro169Ala	missense	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.844C>G	p.Pro282Ala	missense	Exon 8 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.844C>G	p.Pro282Ala	missense	Exon 8 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.409+317386C>G		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11184 AN: 152100 Hom.: 477 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0916

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0686

GnomAD2 exomes AF: 0.0711 AC: 17732 AN: 249482 AF XY: 0.0707

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.0797

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.0867

Gnomad FIN exome AF: 0.0560

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0710

GnomAD4 exome AF: 0.0595 AC: 87031 AN: 1461880 Hom.: 2915 Cov.: 32 AF XY: 0.0601 AC XY: 43702 AN XY: 727242

African (AFR) AF: 0.100 AC: 3357 AN: 33480

American (AMR) AF: 0.0797 AC: 3564 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 2579 AN: 26136

East Asian (EAS) AF: 0.0814 AC: 3233 AN: 39700

South Asian (SAS) AF: 0.0875 AC: 7549 AN: 86256

European-Finnish (FIN) AF: 0.0610 AC: 3260 AN: 53420

Middle Eastern (MID) AF: 0.0669 AC: 386 AN: 5768

European-Non Finnish (NFE) AF: 0.0532 AC: 59208 AN: 1112000

Other (OTH) AF: 0.0645 AC: 3895 AN: 60396

GnomAD4 genome AF: 0.0736 AC: 11203 AN: 152218 Hom.: 476 Cov.: 32 AF XY: 0.0739 AC XY: 5500 AN XY: 74410

African (AFR) AF: 0.0960 AC: 3987 AN: 41542

American (AMR) AF: 0.0800 AC: 1222 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3472

East Asian (EAS) AF: 0.0916 AC: 474 AN: 5172

South Asian (SAS) AF: 0.0918 AC: 442 AN: 4814

European-Finnish (FIN) AF: 0.0540 AC: 573 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0575 AC: 3913 AN: 68020

Other (OTH) AF: 0.0683 AC: 144 AN: 2108

Alfa AF: 0.0611 Hom.: 241

Bravo AF: 0.0721

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.0865 AC: 340

ESP6500EA AF: 0.0592 AC: 491

ExAC AF: 0.0743 AC: 8977

Asia WGS AF: 0.0890 AC: 312 AN: 3478

EpiCase AF: 0.0547

EpiControl AF: 0.0549

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.43
Sift	Benign	0.066	T
Sift4G	Benign	0.54	T
Polyphen		0.99	D
Vest4		0.42
ClinPred		0.045	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.78
Mutation Taster		=4/96	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: rs3764340; hg19: chr16-78466437; COSMIC: COSV68347728;