11-11964504-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001018057.2(DKK3):c.1013C>T(p.Ala338Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,514 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (42 hom.)
• Consequence: DKK3 NM_001018057.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.267

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002554059).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1967/152328) while in subpopulation AFR AF= 0.0451 (1874/41574). AF 95% confidence interval is 0.0434. There are 46 homozygotes in gnomad4. There are 942 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKK3	NM_001018057.2	c.1013C>T	p.Ala338Val	missense_variant	7/7	ENST00000683431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKK3	ENST00000683431.1	c.1013C>T	p.Ala338Val	missense_variant	7/7		NM_001018057.2	P1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1956 AN: 152210 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00306 AC: 763 AN: 249746 Hom.: 18 AF XY: 0.00219 AC XY: 296 AN XY: 135350

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00130 AC: 1903 AN: 1461186 Hom.: 42 Cov.: 29 AF XY: 0.00113 AC XY: 824 AN XY: 726930

Gnomad4 AFR exome AF: 0.0463

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.0129 AC: 1967 AN: 152328 Hom.: 46 Cov.: 33 AF XY: 0.0126 AC XY: 942 AN XY: 74482

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00399 Hom.: 6

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00339 AC: 411

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	12
Dann	Benign	0.20
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.084
Sift	Benign	0.76	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.96	D;D;D
Vest4		0.18
MVP		0.38
MPC		0.33
ClinPred		0.021	T
GERP RS		-2.4
Varity_R		0.013
gMVP		0.21

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: rs114429255; hg19: chr11-11986051;