16-78115103-C-T

Variant names:

• chr16-78115103-C-T
• rs141361080
• NM_016373.4:c.358C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016373.4(WWOX):​c.358C>T​(p.Arg120Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00743 in 1,614,110 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (66 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.54
• Publications: 17 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=0.014221847).
• BP6: Variant 16-78115103-C-T is Benign according to our data. Variant chr16-78115103-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00572 (870/152222) while in subpopulation SAS AF = 0.0164 (79/4816). AF 95% confidence interval is 0.0135. There are 5 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.358C>T	p.Arg120Trp	missense	Exon 4 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.19C>T	p.Arg7Trp	missense	Exon 3 of 8	NP_001278926.1
	WWOX	NM_130791.5		c.358C>T	p.Arg120Trp	missense	Exon 4 of 6	NP_570607.1	Q9NZC7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.358C>T	p.Arg120Trp	missense	Exon 4 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.358C>T	p.Arg120Trp	missense	Exon 4 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.358C>T	p.Arg120Trp	missense	Exon 4 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152104 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00775

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00749 AC: 1869 AN: 249524 AF XY: 0.00803

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00867

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00761 AC: 11121 AN: 1461888 Hom.: 66 Cov.: 34 AF XY: 0.00778 AC XY: 5656 AN XY: 727246

African (AFR) AF: 0.00173 AC: 58 AN: 33480

American (AMR) AF: 0.00313 AC: 140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26136

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.0169 AC: 1460 AN: 86258

European-Finnish (FIN) AF: 0.0101 AC: 537 AN: 53420

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.00754 AC: 8389 AN: 1112006

Other (OTH) AF: 0.00684 AC: 413 AN: 60396

GnomAD4 genome AF: 0.00572 AC: 870 AN: 152222 Hom.: 5 Cov.: 32 AF XY: 0.00624 AC XY: 464 AN XY: 74412

African (AFR) AF: 0.00154 AC: 64 AN: 41538

American (AMR) AF: 0.00634 AC: 97 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5172

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4816

European-Finnish (FIN) AF: 0.00775 AC: 82 AN: 10586

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00772 AC: 525 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00662 Hom.: 19

Bravo AF: 0.00461

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00162 AC: 6

ESP6500EA AF: 0.00758 AC: 62

ExAC AF: 0.00756 AC: 914

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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	WWOX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.87
ClinPred		0.025	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.70
Mutation Taster		=97/3	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: rs141361080; hg19: chr16-78149000;