Genetic Variant DKK3:c.528+43A>G (chr11-11968352-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001018057.2(DKK3):c.528+43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,568,884 control chromosomes in the GnomAD database, including 538,430 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.85 ( 55380 hom., cov: 31)

Exomes 𝑓: 0.82 ( 483050 hom. )

Consequence

DKK3
NM_001018057.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.526

Publications

18 publications found

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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new If you want to explore the variant's impact on the transcript NM_001018057.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018057.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DKK3	NM_001018057.2	MANE Select	c.528+43A>G	intron	N/A	NP_001018067.1	Q9UBP4
DKK3	NM_001330220.3		c.528+43A>G	intron	N/A	NP_001317149.1	F6SYF8
DKK3	NM_013253.5		c.528+43A>G	intron	N/A	NP_037385.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DKK3	ENST00000683431.1	MANE Select	c.528+43A>G	intron	N/A	ENSP00000506835.1	Q9UBP4
DKK3	ENST00000326932.8	TSL:1	c.528+43A>G	intron	N/A	ENSP00000314910.4	Q9UBP4
DKK3	ENST00000396505.7	TSL:1	c.528+43A>G	intron	N/A	ENSP00000379762.2	Q9UBP4

Frequencies

GnomAD3 genomes

AF:

0.851

AC:

129299

AN:

151964

Hom.:

55311

Cov.:

show subpopulations

Gnomad AFR

AF:

0.932

Gnomad AMI

AF:

0.795

Gnomad AMR

AF:

0.895

Gnomad ASJ

AF:

0.921

Gnomad EAS

AF:

0.715

Gnomad SAS

AF:

0.850

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.978

Gnomad NFE

AF:

0.816

Gnomad OTH

AF:

0.859

GnomAD2 exomes

AF:

0.834

AC:

186590

AN:

223696

AF XY:

0.831

show subpopulations

Gnomad AFR exome

AF:

0.934

Gnomad AMR exome

AF:

0.930

Gnomad ASJ exome

AF:

0.923

Gnomad EAS exome

AF:

0.718

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.811

Gnomad OTH exome

AF:

0.854

GnomAD4 exome

AF:

0.824

AC:

1167950

AN:

1416802

Hom.:

483050

Cov.:

AF XY:

0.825

AC XY:

578782

AN XY:

701388

show subpopulations

African (AFR)

AF:

0.937

AC:

30135

AN:

32172

American (AMR)

AF:

0.926

AC:

38436

AN:

41496

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

22225

AN:

24232

East Asian (EAS)

AF:

0.712

AC:

27001

AN:

37902

South Asian (SAS)

AF:

0.866

AC:

70474

AN:

81396

European-Finnish (FIN)

AF:

0.740

AC:

38077

AN:

51444

Middle Eastern (MID)

AF:

0.961

AC:

5359

AN:

5576

European-Non Finnish (NFE)

AF:

0.818

AC:

887169

AN:

1084154

Other (OTH)

AF:

0.840

AC:

49074

AN:

58430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

9867

19735

29602

39470

49337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20718

41436

62154

82872

103590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.851

AC:

129426

AN:

152082

Hom.:

55380

Cov.:

AF XY:

0.849

AC XY:

63139

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.933

AC:

38700

AN:

41500

American (AMR)

AF:

0.896

AC:

13699

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.921

AC:

3192

AN:

3466

East Asian (EAS)

AF:

0.715

AC:

3673

AN:

5136

South Asian (SAS)

AF:

0.850

AC:

4089

AN:

4812

European-Finnish (FIN)

AF:

0.735

AC:

7777

AN:

10588

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

0.816

AC:

55464

AN:

67968

Other (OTH)

AF:

0.862

AC:

1822

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

960

1919

2879

3838

4798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.841

Hom.:

65043

Bravo

AF:

0.866

Asia WGS

AF:

0.811

AC:

2821

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

2.0

(source)

DANN

Benign

0.30

PhyloP100

-0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over