NM_001018057.2:c.1003A>G

Variant names:

• chr11-11964514-T-C
• rs3206824
• NM_001018057.2:c.1003A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 48 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DKK3	NM_001018057.2	c.1003A>G	p.Arg335Gly	missense_variant	Exon 7 of 7	ENST00000683431.1	NP_001018067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK3	ENST00000683431.1	c.1003A>G	p.Arg335Gly	missense_variant	Exon 7 of 7		NM_001018057.2	ENSP00000506835.1

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

GnomAD2 exomes AF: 0.785 AC: 196727 AN: 250656 AF XY: 0.783

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 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

African (AFR) AF: 0.818 AC: 27403 AN: 33480

American (AMR) AF: 0.898 AC: 40173 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 23040 AN: 26136

East Asian (EAS) AF: 0.771 AC: 30608 AN: 39700

South Asian (SAS) AF: 0.840 AC: 72483 AN: 86256

European-Finnish (FIN) AF: 0.639 AC: 33847 AN: 52940

Middle Eastern (MID) AF: 0.916 AC: 5281 AN: 5768

European-Non Finnish (NFE) AF: 0.749 AC: 833315 AN: 1111992

Other (OTH) AF: 0.784 AC: 47329 AN: 60368

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

African (AFR) AF: 0.817 AC: 33956 AN: 41538

American (AMR) AF: 0.857 AC: 13129 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3064 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4094 AN: 5168

South Asian (SAS) AF: 0.836 AC: 4035 AN: 4828

European-Finnish (FIN) AF: 0.634 AC: 6718 AN: 10590

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50960 AN: 68000

Other (OTH) AF: 0.803 AC: 1697 AN: 2114

Alfa AF: 0.772 Hom.: 165626

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;.
PhyloP100		-0.36
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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