rs74944733

chr16-78386890-G-Achr16-78386890-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):c.547G>A(p.Asp183Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00407 in 1,614,010 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D183H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (97 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.93

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00798434).
• BP6: Variant 16-78386890-G-A is Benign according to our data. Variant chr16-78386890-G-A is described in ClinVar as [Benign]. Clinvar id is 260741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.547G>A	p.Asp183Asn	missense_variant	6/9	ENST00000566780.6
WWOX	NM_001291997.2	c.208G>A	p.Asp70Asn	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.547G>A	p.Asp183Asn	missense_variant	6/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3423 AN: 152052 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00826

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00561 AC: 1399 AN: 249366 Hom.: 49 AF XY: 0.00449 AC XY: 607 AN XY: 135280

Gnomad AFR exome AF: 0.0785

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00215 AC: 3146 AN: 1461838 Hom.: 97 Cov.: 34 AF XY: 0.00184 AC XY: 1338 AN XY: 727224

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.0225 AC: 3427 AN: 152172 Hom.: 135 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74402

Gnomad4 AFR AF: 0.0784

Gnomad4 AMR AF: 0.00825

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00401 Hom.: 24

Bravo AF: 0.0260

ESP6500AA AF: 0.0672 AC: 262

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.00710 AC: 858

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.1	D;D
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.93	P;.
Vest4		0.72
MVP		0.96
ClinPred		0.019	T
GERP RS		5.5
Varity_R		0.57
gMVP		0.65

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: rs74944733; hg19: chr16-78420787;