8-42374300-G-C

Variant names:

• chr8-42374300-G-C
• rs766494052
• NM_014420.3:c.475C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014420.3(DKK4):​c.475C>G​(p.Arg159Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DKK4 NM_014420.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.93

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKK4	NM_014420.3	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 4	ENST00000220812.3	NP_055235.1
DKK4	XM_011544488.3	c.475C>G	p.Arg159Gly	missense_variant	Exon 5 of 5		XP_011542790.1
DKK4	XM_017013316.2	c.475C>G	p.Arg159Gly	missense_variant	Exon 5 of 5		XP_016868805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKK4	ENST00000220812.3	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 4	1	NM_014420.3	ENSP00000220812.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.55		Loss of stability (P = 0.0337);
MVP		0.96
MPC		0.71
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766494052; hg19: chr8-42231818;