11-11968418-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001018057.2(DKK3):c.505C>A(p.Gln169Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 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)
• Consequence: DKK3 NM_001018057.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKK3	NM_001018057.2	c.505C>A	p.Gln169Lys	missense_variant	4/7	ENST00000683431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKK3	ENST00000683431.1	c.505C>A	p.Gln169Lys	missense_variant	4/7		NM_001018057.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfanoid habitus and intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Benign	0.85
DEOGEN2	Benign	0.15	T;T;.;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.66	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.51	P;P;P;.;.
Vest4		0.31
MutPred		0.82		Gain of catalytic residue at Q169 (P = 0.0099);Gain of catalytic residue at Q169 (P = 0.0099);Gain of catalytic residue at Q169 (P = 0.0099);Gain of catalytic residue at Q169 (P = 0.0099);.;
MVP		0.60
MPC		0.82
ClinPred		0.52	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.76

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

Other links and lift over

dbSNP: rs1590500384; hg19: chr11-11989965;