rs376935572

chr16-79211748-G-Achr16-79211748-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The ENST00000402655.6(WWOX):c.550G>A(p.Ala184Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 1,614,202 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict 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. A184S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (3 hom.)
• Consequence: WWOX ENST00000402655.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.405

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]

MAF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004627943).
• BP6: Variant 16-79211748-G-A is Benign according to our data. Variant chr16-79211748-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-79211748-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00192 (293/152320) while in subpopulation AMR AF= 0.00497 (76/15300). AF 95% confidence interval is 0.00407. There are 0 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1197G>A	p.Ala399=	synonymous_variant	9/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1197G>A	p.Ala399=	synonymous_variant	9/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000890 AC: 222 AN: 249444 Hom.: 0 AF XY: 0.000872 AC XY: 118 AN XY: 135380

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000638 AC: 932 AN: 1461882 Hom.: 3 Cov.: 88 AF XY: 0.000623 AC XY: 453 AN XY: 727246

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000526

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74474

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00240

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00353 AC: 14

ESP6500EA AF: 0.000602 AC: 5

ExAC AF: 0.000695 AC: 84

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	WWOX: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive spinocerebellar ataxia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.69
Dann	Benign	0.90
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	0.040	N
REVEL	Benign	0.022
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		0.0060	B
Vest4		0.093
MVP		0.39
ClinPred		0.0059	T
GERP RS		-5.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs376935572; hg19: chr16-79245645;