rs76204496

chr16-79211779-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_016373.4(WWOX):c.1228G>T(p.Gly410Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,942 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G410G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (4 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.85

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036941916).
• BP6: Variant 16-79211779-G-T is Benign according to our data. Variant chr16-79211779-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506528.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000295 (431/1461636) while in subpopulation MID AF= 0.004 (23/5752). AF 95% confidence interval is 0.00273. There are 4 homozygotes in gnomad4_exome. There are 263 alleles in male gnomad4_exome subpopulation. Median coverage is 89. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1228G>T	p.Gly410Cys	missense_variant	9/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1228G>T	p.Gly410Cys	missense_variant	9/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000525 AC: 130 AN: 247696 Hom.: 1 AF XY: 0.000631 AC XY: 85 AN XY: 134674

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461636 Hom.: 4 Cov.: 89 AF XY: 0.000362 AC XY: 263 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00275

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000926

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74478

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	This variant is associated with the following publications: (PMID: 27121845) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	WWOX: BP4, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 29, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N
Sift	Uncertain	0.0080	D;T
Sift4G	Uncertain	0.020	D;T
Polyphen		0.96	D;D
Vest4		0.32
MVP		0.92
ClinPred		0.058	T
GERP RS		4.7
Varity_R		0.23
gMVP		0.46

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: rs76204496; hg19: chr16-79245676;