rs114755364

Variant names:

• chr16-78115077-C-G
• rs114755364
• NM_016373.4:c.332C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-78115077-C-G
• chr16-78115077-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016373.4(WWOX):​c.332C>G​(p.Thr111Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000554 in 1,614,186 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T111I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.63
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008024842).
• BP6: Variant 16-78115077-C-G is Benign according to our data. Variant chr16-78115077-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 383820.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00297 (452/152302) while in subpopulation AFR AF = 0.0104 (432/41560). AF 95% confidence interval is 0.00958. There are 1 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.332C>G	p.Thr111Ser	missense	Exon 4 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_130791.5		c.332C>G	p.Thr111Ser	missense	Exon 4 of 6	NP_570607.1	Q9NZC7-3
	WWOX	NM_001291997.2		c.-8C>G		5_prime_UTR	Exon 3 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.332C>G	p.Thr111Ser	missense	Exon 4 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.332C>G	p.Thr111Ser	missense	Exon 4 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.332C>G	p.Thr111Ser	missense	Exon 4 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000713 AC: 178 AN: 249566 AF XY: 0.000487

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000302 AC: 442 AN: 1461884 Hom.: 4 Cov.: 34 AF XY: 0.000263 AC XY: 191 AN XY: 727244

African (AFR) AF: 0.0112 AC: 376 AN: 33478

American (AMR) AF: 0.000291 AC: 13 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112006

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74466

African (AFR) AF: 0.0104 AC: 432 AN: 41560

American (AMR) AF: 0.000784 AC: 12 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00354

ESP6500AA AF: 0.0116 AC: 43

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000819 AC: 99

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.010	N
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.30
MutPred		0.26		Loss of glycosylation at T111 (P = 0.0634)
MVP		0.87
ClinPred		0.039	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.59
Mutation Taster		=78/22	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: rs114755364; hg19: chr16-78148974;