Variant 11-11964657-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001018057.2(DKK3):c.860C>T(p.Thr287Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

DKK3
NM_001018057.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11

Variant links:

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]

DKK3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052100003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKK3	NM_001018057.2 linkuse as main transcript	c.860C>T	p.Thr287Ile	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 linkuse as main transcript	c.860C>T	p.Thr287Ile	missense_variant	7/7		NM_001018057.2	ENSP00000506835	P1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

251008

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000762

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.860C>T (p.T287I) alteration is located in exon 8 (coding exon 7) of the DKK3 gene. This alteration results from a C to T substitution at nucleotide position 860, causing the threonine (T) at amino acid position 287 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.48

N;N;N

REVEL

Benign

0.056

Sift

Benign

0.054

T;T;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.45

P;P;P

Vest4

0.071

MVP

0.18

MPC

0.39

ClinPred

0.036

GERP RS

4.6

Varity_R

0.051

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over