rs188317479

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001018057.2(DKK3):​c.689T>G​(p.Val230Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V230A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DKK3
NM_001018057.2 missense

Scores

12
3
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.91

Publications

0 publications found
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK3NM_001018057.2 linkc.689T>G p.Val230Gly 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
DKK3ENST00000683431.1 linkc.689T>G p.Val230Gly missense_variant Exon 6 of 7 NM_001018057.2 ENSP00000506835.1 Q9UBP4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460532
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726534
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86194
European-Finnish (FIN)
AF:
0.0000191
AC:
1
AN:
52454
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111826
Other (OTH)
AF:
0.00
AC:
0
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;D;.;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
.;T;T;T
M_CAP
Benign
0.058
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.6
M;M;.;.
PhyloP100
8.9
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.7
D;D;D;D
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
D;D;D;.
Vest4
0.71
MutPred
0.69
Loss of stability (P = 0.0163);Loss of stability (P = 0.0163);Loss of stability (P = 0.0163);Loss of stability (P = 0.0163);
MVP
0.91
MPC
1.2
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.91
gMVP
0.96
Mutation Taster
=8/92
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs188317479; hg19: chr11-11987497; API