rs34944716

Variant names:

• chr16-78115096-C-G
• rs34944716
• NM_016373.4:c.351C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-78115096-C-G
• chr16-78115096-C-T
• chr16-78115096-C-A

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.351C>G​(p.Leu117Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,146 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L117L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: WWOX NM_016373.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.586
• Publications: 4 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 (BayesDel_noAF=-0.44).
• BP6: Variant 16-78115096-C-G is Benign according to our data. Variant chr16-78115096-C-G is described in ClinVar as Benign. ClinVar VariationId is 241102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.586 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1727/152260) while in subpopulation AFR AF = 0.0382 (1588/41544). AF 95% confidence interval is 0.0367. There are 35 homozygotes in GnomAd4. There are 823 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.351C>G	p.Leu117Leu	synonymous	Exon 4 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.12C>G	p.Leu4Leu	synonymous	Exon 3 of 8	NP_001278926.1
	WWOX	NM_130791.5		c.351C>G	p.Leu117Leu	synonymous	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.351C>G	p.Leu117Leu	synonymous	Exon 4 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.351C>G	p.Leu117Leu	synonymous	Exon 4 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.351C>G	p.Leu117Leu	synonymous	Exon 4 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1727 AN: 152142 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00267 AC: 666 AN: 249532 AF XY: 0.00194

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1461886 Hom.: 30 Cov.: 34 AF XY: 0.000947 AC XY: 689 AN XY: 727244

African (AFR) AF: 0.0360 AC: 1204 AN: 33480

American (AMR) AF: 0.00244 AC: 109 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: 0.000104 AC: 9 AN: 86256

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

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112006

Other (OTH) AF: 0.00308 AC: 186 AN: 60396

GnomAD4 genome AF: 0.0113 AC: 1727 AN: 152260 Hom.: 35 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74450

African (AFR) AF: 0.0382 AC: 1588 AN: 41544

American (AMR) AF: 0.00739 AC: 113 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00345 Hom.: 4

Bravo AF: 0.0127

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs34944716; hg19: chr16-78148993;