rs201984841

Variant names:

• chr8-42375773-G-A
• rs201984841
• NM_014420.3:c.169C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-42375773-G-A
• chr8-42375773-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014420.3(DKK4):​c.169C>T​(p.Arg57Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: DKK4 NM_014420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 1 publications found

Genes affected

DKK4 (HGNC:2894): (dickkopf WNT signaling pathway inhibitor 4) 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. Activity of this protein is modulated by binding to the Wnt co-receptor and the co-factor kremen 2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039660037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK4	NM_014420.3	MANE Select	c.169C>T	p.Arg57Cys	missense	Exon 2 of 4	NP_055235.1	Q9UBT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK4	ENST00000220812.3	TSL:1 MANE Select	c.169C>T	p.Arg57Cys	missense	Exon 2 of 4	ENSP00000220812.2	Q9UBT3

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000169 AC: 42 AN: 248884 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727204

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112002

Other (OTH) AF: 0.0000828 AC: 5 AN: 60390

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.00248 AC: 38 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000257

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.097
Sift	Benign	0.077	T
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.33
MutPred		0.41		Loss of solvent accessibility (P = 6e-04)
MVP		0.50
MPC		0.65
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.15
gMVP		0.87
Mutation Taster		=91/9	polymorphism

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: rs201984841; hg19: chr8-42233291; COSMIC: COSV55183194; COSMIC: COSV55183194;