chr11-11967089-G-C

Variant names:

• chr11-11967089-G-C
• rs371884398
• NM_001018057.2:c.538C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001018057.2(DKK3):​c.538C>G​(p.Arg180Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,164 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DKK3 NM_001018057.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK3	NM_001018057.2	c.538C>G	p.Arg180Gly	missense_variant	Exon 5 of 7	ENST00000683431.1	NP_001018067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK3	ENST00000683431.1	c.538C>G	p.Arg180Gly	missense_variant	Exon 5 of 7		NM_001018057.2	ENSP00000506835.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461164 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.88	.;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.65
MutPred		0.87		Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);.;
MVP		0.62
MPC		1.2
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.63
gMVP		0.88

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: rs371884398; hg19: chr11-11988636;