rs202002431

chr16-79211693-G-Achr16-79211693-G-Cchr16-79211693-G-T

Variant summary

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

The NM_016373.4(WWOX):c.1142G>A(p.Arg381His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,208 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R381C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.25

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=0.04400131).
• BP6: Variant 16-79211693-G-A is Benign according to our data. Variant chr16-79211693-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 410089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000385 (563/1461890) while in subpopulation AMR AF= 0.00134 (60/44724). AF 95% confidence interval is 0.00112. There are 2 homozygotes in gnomad4_exome. There are 301 alleles in male gnomad4_exome subpopulation. Median coverage is 88. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1142G>A	p.Arg381His	missense_variant	9/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1142G>A	p.Arg381His	missense_variant	9/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000565 AC: 141 AN: 249548 Hom.: 1 AF XY: 0.000532 AC XY: 72 AN XY: 135402

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1461890 Hom.: 2 Cov.: 88 AF XY: 0.000414 AC XY: 301 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74462

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000637 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

WWOX-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2019

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.059	T
Vest4		0.37
MVP		0.91
ClinPred		0.058	T
GERP RS		5.7

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: rs202002431; hg19: chr16-79245590;