Variant X-10109984-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015691.5(WWC3):c.1310G>A(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,207,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000023 ( 0 hom. 11 hem. )

Consequence

WWC3
NM_015691.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

WWC3 (HGNC:29237): (WWC family member 3) This gene encodes a member of the WWC family of proteins, which also includes the WWC1 (KIBRA) gene product and the WWC2 gene product. The protein encoded by this gene includes a C2 domain, which is known to mediate homodimerization in the related WWC1 gene product. [provided by RefSeq, Sep 2011]

WWC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1961768).

BS2

High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWC3	NM_015691.5 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	10/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWC3	ENST00000380861.10 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	10/24	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112199

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34343

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000173

AC:

AN:

173465

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

63253

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:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1094995

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

361883

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000740

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112199

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34343

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.938G>A (p.R313H) alteration is located in exon 9 (coding exon 8) of the WWC3 gene. This alteration results from a G to A substitution at nucleotide position 938, causing the arginine (R) at amino acid position 313 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.027

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.29

M_CAP

Benign

0.018

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

REVEL

Benign

0.11

Sift

Benign

0.085

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.31

MutPred

0.23

Loss of MoRF binding (P = 0.0221);

MVP

0.31

MPC

0.94

ClinPred

0.59

GERP RS

5.6

Varity_R

0.14

gMVP

0.088

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over