rs11545028

Variant names:

• chr16-78099774-C-T
• rs11545028
• NM_016373.4:c.-5C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.-5C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,541,828 control chromosomes in the GnomAD database, including 80,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6339 hom., cov: 33)
  • Exomes 𝑓: 0.32 (74319 hom.)
• Consequence: WWOX NM_016373.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.258
• Publications: 30 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-78099774-C-T is Benign according to our data. Variant chr16-78099774-C-T is described in ClinVar as Benign. ClinVar VariationId is 260735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 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.-5C>T		5_prime_UTR	Exon 1 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.-279C>T		5_prime_UTR	Exon 1 of 8	NP_001278926.1
	WWOX	NM_130791.5		c.-5C>T		5_prime_UTR	Exon 1 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.-5C>T		5_prime_UTR	Exon 1 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.-5C>T		5_prime_UTR	Exon 1 of 10	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.-5C>T		5_prime_UTR	Exon 1 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42307 AN: 152068 Hom.: 6335 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.300 AC: 44471 AN: 148386 AF XY: 0.301

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.324 AC: 449999 AN: 1389642 Hom.: 74319 Cov.: 34 AF XY: 0.322 AC XY: 220932 AN XY: 685744

African (AFR) AF: 0.161 AC: 4926 AN: 30634

American (AMR) AF: 0.254 AC: 8469 AN: 33354

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 8892 AN: 24558

East Asian (EAS) AF: 0.209 AC: 7289 AN: 34938

South Asian (SAS) AF: 0.255 AC: 19773 AN: 77680

European-Finnish (FIN) AF: 0.352 AC: 17320 AN: 49218

Middle Eastern (MID) AF: 0.260 AC: 1288 AN: 4948

European-Non Finnish (NFE) AF: 0.338 AC: 364188 AN: 1076806

Other (OTH) AF: 0.310 AC: 17854 AN: 57506

GnomAD4 genome AF: 0.278 AC: 42315 AN: 152186 Hom.: 6339 Cov.: 33 AF XY: 0.277 AC XY: 20642 AN XY: 74400

African (AFR) AF: 0.162 AC: 6745 AN: 41542

American (AMR) AF: 0.263 AC: 4026 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1296 AN: 3468

East Asian (EAS) AF: 0.220 AC: 1132 AN: 5148

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4828

European-Finnish (FIN) AF: 0.364 AC: 3863 AN: 10600

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23128 AN: 67978

Other (OTH) AF: 0.269 AC: 568 AN: 2114

Alfa AF: 0.318 Hom.: 17933

Bravo AF: 0.268

Asia WGS AF: 0.191 AC: 665 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		0.26
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11545028; hg19: chr16-78133671; COSMIC: COSV63434361; COSMIC: COSV63434361;