rs3206824

Positions:

• chr11-11964514-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001018057.2(DKK3):​c.1003A>G​(p.Arg335Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,613,592 control chromosomes in the GnomAD database, including 472,939 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.78 (46483 hom., cov: 34)
  • Exomes 𝑓: 0.76 (426456 hom.)
• Consequence: DKK3 NM_001018057.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.360

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.1718243E-7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKK3	NM_001018057.2	c.1003A>G	p.Arg335Gly	missense_variant	7/7	ENST00000683431.1	NP_001018067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKK3	ENST00000683431.1	c.1003A>G	p.Arg335Gly	missense_variant	7/7		NM_001018057.2	ENSP00000506835	P1

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118428 AN: 152110 Hom.: 46446 Cov.: 34

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.799

GnomAD3 exomes AF: 0.785 AC: 196727 AN: 250656 Hom.: 78079 AF XY: 0.783 AC XY: 106165 AN XY: 135572

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.886

Gnomad EAS exome AF: 0.804

Gnomad SAS exome AF: 0.841

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.745

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.762 AC: 1113479 AN: 1461364 Hom.: 426456 Cov.: 75 AF XY: 0.763 AC XY: 555006 AN XY: 727002

Gnomad4 AFR exome AF: 0.818

Gnomad4 AMR exome AF: 0.898

Gnomad4 ASJ exome AF: 0.882

Gnomad4 EAS exome AF: 0.771

Gnomad4 SAS exome AF: 0.840

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.749

Gnomad4 OTH exome AF: 0.784

GnomAD4 genome AF: 0.779 AC: 118521 AN: 152228 Hom.: 46483 Cov.: 34 AF XY: 0.778 AC XY: 57922 AN XY: 74428

Gnomad4 AFR AF: 0.817

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.836

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.749

Gnomad4 OTH AF: 0.803

Alfa AF: 0.770 Hom.: 107381

Bravo AF: 0.797

TwinsUK AF: 0.752 AC: 2788

ALSPAC AF: 0.755 AC: 2911

ESP6500AA AF: 0.811 AC: 3570

ESP6500EA AF: 0.752 AC: 6456

ExAC AF: 0.776 AC: 93573

Asia WGS AF: 0.817 AC: 2842 AN: 3476

EpiCase AF: 0.767

EpiControl AF: 0.773

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.14
DEOGEN2	Benign	0.061	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.088	.;T;T
MetaRNN	Benign	9.2e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.62	N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.69	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.036
MPC		0.42
ClinPred		0.00013	T
GERP RS		-2.6
Varity_R		0.042
gMVP		0.22

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: rs3206824; hg19: chr11-11986061; COSMIC: COSV58867726; COSMIC: COSV58867726;