chr16-78099797-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016373.4(WWOX):​c.19G>A​(p.Ala7Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000747 in 1,565,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23368603).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WWOXNM_016373.4 linkuse as main transcriptc.19G>A p.Ala7Thr missense_variant 1/9 ENST00000566780.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WWOXENST00000566780.6 linkuse as main transcriptc.19G>A p.Ala7Thr missense_variant 1/91 NM_016373.4 P1Q9NZC7-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000566
AC:
10
AN:
176566
Hom.:
0
AF XY:
0.0000733
AC XY:
7
AN XY:
95462
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000245
Gnomad NFE exome
AF:
0.0000786
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000743
AC:
105
AN:
1413792
Hom.:
0
Cov.:
31
AF XY:
0.0000586
AC XY:
41
AN XY:
699724
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000271
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000259
Gnomad4 NFE exome
AF:
0.0000826
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000235
AC:
2
ExAC
AF:
0.0000421
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 19, 2022This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 7 of the WWOX protein (p.Ala7Thr). This variant is present in population databases (rs371392600, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1424743). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Uncertain
0.035
T
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;T;.;.;T;.;.;.
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.23
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Benign
-0.090
N;.;N;N;.;N;N;N
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.71
N;.;N;N;N;N;N;N
REVEL
Benign
0.23
Sift
Benign
0.16
T;.;D;T;D;D;D;T
Sift4G
Uncertain
0.034
D;D;D;D;D;D;D;D
Polyphen
0.65
P;.;D;P;.;P;P;.
Vest4
0.64
MVP
0.94
ClinPred
0.33
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.27
gMVP
0.29

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371392600; hg19: chr16-78133694; API