11-11964685-G-C

Variant summary

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

The NM_001018057.2(DKK3):c.832C>G(p.His278Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DKK3 NM_001018057.2 missense, splice_region
• Scores: Splicing: ADA: 0.9738
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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.832C>G	p.His278Asp	missense_variant, splice_region_variant	7/7	ENST00000683431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKK3	ENST00000683431.1	c.832C>G	p.His278Asp	missense_variant, splice_region_variant	7/7		NM_001018057.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.832C>G (p.H278D) alteration is located in exon 8 (coding exon 7) of the DKK3 gene. This alteration results from a C to G substitution at nucleotide position 832, causing the histidine (H) at amino acid position 278 to be replaced by an aspartic acid (D). 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	0.20
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;D;N
REVEL	Benign	0.15
Sift	Uncertain	0.020	D;D;T
Sift4G	Uncertain	0.038	D;D;T
Polyphen		0.65	P;P;P
Vest4		0.64
MutPred		0.26		.;.;Gain of disorder (P = 0.0562);
MVP		0.28
MPC		0.89
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-11986232;