rs79771882

Variant names:

• chr16-78432581-G-A
• rs79771882
• NM_016373.4:c.885G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_016373.4(WWOX):​c.885G>A​(p.Arg295Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,140 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (101 hom.)
• Consequence: WWOX NM_016373.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0280
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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 (REVEL=0.05).
• BP6: Variant 16-78432581-G-A is Benign according to our data. Variant chr16-78432581-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212617.
• BP7: Synonymous conserved (PhyloP=-0.028 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00899 (1368/152252) while in subpopulation NFE AF = 0.00806 (548/68030). AF 95% confidence interval is 0.0075. There are 13 homozygotes in GnomAd4. There are 757 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.885G>A	p.Arg295Arg	synonymous	Exon 8 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.546G>A	p.Arg182Arg	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.885G>A	p.Arg295Arg	synonymous	Exon 8 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.885G>A	p.Arg295Arg	synonymous	Exon 8 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.409+317427G>A		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1369 AN: 152132 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00857 AC: 2139 AN: 249566 AF XY: 0.00840

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.00779

Gnomad OTH exome AF: 0.00957

GnomAD4 exome AF: 0.00890 AC: 13013 AN: 1461888 Hom.: 101 Cov.: 32 AF XY: 0.00862 AC XY: 6269 AN XY: 727246

African (AFR) AF: 0.00741 AC: 248 AN: 33480

American (AMR) AF: 0.00434 AC: 194 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86258

European-Finnish (FIN) AF: 0.0370 AC: 1979 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00890 AC: 9899 AN: 1112010

Other (OTH) AF: 0.00758 AC: 458 AN: 60396

GnomAD4 genome AF: 0.00899 AC: 1368 AN: 152252 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 757 AN XY: 74422

African (AFR) AF: 0.00604 AC: 251 AN: 41544

American (AMR) AF: 0.00543 AC: 83 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.0416 AC: 441 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00806 AC: 548 AN: 68030

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00782 Hom.: 4

Bravo AF: 0.00641

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00812

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	WWOX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.2
DANN	Benign	0.68
PhyloP100		-0.028
Mutation Taster		=100/0	polymorphism

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: rs79771882; hg19: chr16-78466478;