Genetic Variant DKK3:p.Val236Met (chr11-11965933-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001018057.2(DKK3):c.706G>A(p.Val236Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

DKK3
NM_001018057.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.196

Variant links:

Genes affected

DKK3 (HGNC:2893): (dickkopf WNT signaling pathway inhibitor 3) This gene encodes a protein that is a member of the dickkopf family. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. The expression of this gene is decreased in a variety of cancer cell lines and it may function as a tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

DKK3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024234384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK3	NM_001018057.2 link	c.706G>A	p.Val236Met	missense_variant	Exon 6 of 7	ENST00000683431.1	NP_001018067.1	Q9UBP4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK3	ENST00000683431.1 link	c.706G>A	p.Val236Met	missense_variant	Exon 6 of 7		NM_001018057.2	ENSP00000506835.1		Q9UBP4

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249132

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134876

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000118

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000222

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.706G>A (p.V236M) alteration is located in exon 7 (coding exon 6) of the DKK3 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the valine (V) at amino acid position 236 to be replaced by a methionine (M). 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

0.085

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.024

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.29

B;B;P

Vest4

0.30

MVP

0.32

MPC

0.37

ClinPred

0.019

GERP RS

2.9

Varity_R

0.030

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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