chr11-11964477-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001018057.2(DKK3):​c.1040G>A​(p.Gly347Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DKK3
NM_001018057.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

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]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12931395).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DKK3NM_001018057.2 linkc.1040G>A p.Gly347Glu missense_variant Exon 7 of 7 ENST00000683431.1 NP_001018067.1 Q9UBP4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DKK3ENST00000683431.1 linkc.1040G>A p.Gly347Glu missense_variant Exon 7 of 7 NM_001018057.2 ENSP00000506835.1 Q9UBP4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459786
Hom.:
0
Cov.:
29
AF XY:
0.00000275
AC XY:
2
AN XY:
726328
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111968
Other (OTH)
AF:
0.00
AC:
0
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 11, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1040G>A (p.G347E) alteration is located in exon 8 (coding exon 7) of the DKK3 gene. This alteration results from a G to A substitution at nucleotide position 1040, causing the glycine (G) at amino acid position 347 to be replaced by a glutamic acid (E). 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
0.080
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
T;T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.49
.;T;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.8
L;L;.
PhyloP100
1.2
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.20
N;N;N
REVEL
Benign
0.042
Sift
Uncertain
0.012
D;D;D
Sift4G
Benign
0.081
T;T;T
Polyphen
0.0050
B;B;B
Vest4
0.22
MutPred
0.22
.;.;Gain of solvent accessibility (P = 0.024);
MVP
0.48
MPC
0.42
ClinPred
0.51
D
GERP RS
3.0
Varity_R
0.048
gMVP
0.64
Mutation Taster
=88/12
polymorphism

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

Other links and lift over

dbSNP: rs1847531030; hg19: chr11-11986024; API