Variant 3-184155729-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004423.4(DVL3):c.94G>A(p.Asp32Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DVL3
NM_004423.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89

Variant links:

Genes affected

DVL3 (HGNC:3087): (dishevelled segment polarity protein 3) This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation. [provided by RefSeq, Jul 2008]

DVL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DVL3	NM_004423.4 linkuse as main transcript	c.94G>A	p.Asp32Asn	missense_variant	1/15	ENST00000313143.9	NP_004414.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DVL3	ENST00000313143.9 linkuse as main transcript	c.94G>A	p.Asp32Asn	missense_variant	1/15	1	NM_004423.4	ENSP00000316054	P1	Q92997-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249578

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134984

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:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461010

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726780

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DVL3 protein function. This variant has not been reported in the literature in individuals affected with DVL3-related conditions. This variant is present in population databases (rs769526852, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 32 of the DVL3 protein (p.Asp32Asn). 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.1

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

.;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

.;D;D

Sift4G

Uncertain

0.025

.;D;D

Polyphen

1.0

D;D;.

Vest4

0.61, 0.67

MutPred

0.85

Loss of ubiquitination at K34 (P = 0.0373);Loss of ubiquitination at K34 (P = 0.0373);Loss of ubiquitination at K34 (P = 0.0373);

MVP

0.74

MPC

1.6

ClinPred

0.99

GERP RS

3.5

Varity_R

0.59

gMVP

0.87

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