Menu
GeneBe

8-42374300-G-T

Variant summary

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

The NM_014420.3(DKK4):c.475C>A(p.Arg159Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DKK4
NM_014420.3 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.93
Variant links:
Genes affected
DKK4 (HGNC:2894): (dickkopf WNT signaling pathway inhibitor 4) 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. Activity of this protein is modulated by binding to the Wnt co-receptor and the co-factor kremen 2. [provided by RefSeq, Jul 2008]

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, 0.91

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DKK4NM_014420.3 linkuse as main transcriptc.475C>A p.Arg159Ser missense_variant 4/4 ENST00000220812.3
DKK4XM_011544488.3 linkuse as main transcriptc.475C>A p.Arg159Ser missense_variant 5/5
DKK4XM_017013316.2 linkuse as main transcriptc.475C>A p.Arg159Ser missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DKK4ENST00000220812.3 linkuse as main transcriptc.475C>A p.Arg159Ser missense_variant 4/41 NM_014420.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsMay 03, 2023The c.475C>A (p.R159S) alteration is located in exon 4 (coding exon 4) of the DKK4 gene. This alteration results from a C to A substitution at nucleotide position 475, causing the arginine (R) at amino acid position 159 to be replaced by a serine (S). 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.072
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.81
MutPred
0.56
Loss of MoRF binding (P = 0.0721);
MVP
0.96
MPC
0.66
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.87
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs766494052; hg19: chr8-42231818; API