19-46648511-C-A

Variant names:

• chr19-46648511-C-A
• rs2052940226
• NM_145056.3:c.1861G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145056.3(DACT3):​c.1861G>T​(p.Gly621Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

Genes affected

DACT3 (HGNC:30745): (dishevelled binding antagonist of beta catenin 3) Predicted to enable delta-catenin binding activity; protein kinase A binding activity; and protein kinase C binding activity. Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT3	NM_145056.3	c.1861G>T	p.Gly621Cys	missense_variant	Exon 4 of 4	ENST00000391916.7	NP_659493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DACT3	ENST00000391916.7	c.1861G>T	p.Gly621Cys	missense_variant	Exon 4 of 4	5	NM_145056.3	ENSP00000375783.2
DACT3	ENST00000300875.4	c.1186G>T	p.Gly396Cys	missense_variant	Exon 4 of 4	1		ENSP00000300875.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1861G>T (p.G621C) alteration is located in exon 4 (coding exon 4) of the DACT3 gene. This alteration results from a G to T substitution at nucleotide position 1861, causing the glycine (G) at amino acid position 621 to be replaced by a cysteine (C). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.60		.;Loss of catalytic residue at G621 (P = 0.0427);
MVP		0.53
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.89
gMVP		0.78

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: rs2052940226; hg19: chr19-47151768; COSMIC: COSV56258380; COSMIC: COSV56258380;