11-11964597-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001018057.2(DKK3):c.920A>G(p.Glu307Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,614,160 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (106 hom.)
• Consequence: DKK3 NM_001018057.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050218403).
• BP6: Variant 11-11964597-T-C is Benign according to our data. Variant chr11-11964597-T-C is described in ClinVar as [Benign]. Clinvar id is 768428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DKK3	NM_001018057.2	c.920A>G	p.Glu307Gly	missense_variant	7/7	ENST00000683431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DKK3	ENST00000683431.1	c.920A>G	p.Glu307Gly	missense_variant	7/7		NM_001018057.2	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2845 AN: 152160 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00443

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00845 AC: 2126 AN: 251454 Hom.: 30 AF XY: 0.00816 AC XY: 1109 AN XY: 135908

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.00517

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00625 AC: 9139 AN: 1461882 Hom.: 106 Cov.: 36 AF XY: 0.00640 AC XY: 4653 AN XY: 727240

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.00615

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00462

Gnomad4 OTH exome AF: 0.00836

GnomAD4 genome AF: 0.0187 AC: 2854 AN: 152278 Hom.: 69 Cov.: 33 AF XY: 0.0184 AC XY: 1367 AN XY: 74458

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00443

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00681 Hom.: 18

Bravo AF: 0.0205

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.0566 AC: 249

ESP6500EA AF: 0.00524 AC: 45

ExAC AF: 0.00935 AC: 1135

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00575

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.46	N
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.65	P;P;P
Vest4		0.066
MVP		0.41
MPC		0.39
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.10
gMVP		0.52

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: rs114873269; hg19: chr11-11986144;