19-46649300-G-C

Position:

• chr19-46649300-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145056.3(DACT3):​c.1072C>G​(p.Gln358Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000736 in 1,086,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24998093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACT3	NM_145056.3	c.1072C>G	p.Gln358Glu	missense_variant	4/4	ENST00000391916.7	NP_659493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DACT3	ENST00000391916.7	c.1072C>G	p.Gln358Glu	missense_variant	4/4	5	NM_145056.3	ENSP00000375783.2
DACT3	ENST00000300875.4	c.397C>G	p.Gln133Glu	missense_variant	4/4	1		ENSP00000300875.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000736 AC: 8 AN: 1086356 Hom.: 0 Cov.: 31 AF XY: 0.00000572 AC XY: 3 AN XY: 524854

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: 0.00000869

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.1072C>G (p.Q358E) alteration is located in exon 4 (coding exon 4) of the DACT3 gene. This alteration results from a C to G substitution at nucleotide position 1072, causing the glutamine (Q) at amino acid position 358 to be replaced by a glutamic acid (E). 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	0.29
BayesDel_addAF	Benign	-0.0073	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.34	T;T
Polyphen		0.75	.;P
Vest4		0.33
MutPred		0.31		.;Loss of MoRF binding (P = 0.0404);
MVP		0.49
ClinPred		0.64	D
GERP RS		2.7
Varity_R		0.30
gMVP		0.56

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: rs2052954002; hg19: chr19-47152557;