chr19-46649113-T-C

Position:

• chr19-46649113-T-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.1259A>G​(p.Lys420Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,139,178 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: 0.0000018 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214

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=0.2163203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACT3	NM_145056.3	c.1259A>G	p.Lys420Arg	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.1259A>G	p.Lys420Arg	missense_variant	4/4	5	NM_145056.3	ENSP00000375783.2
DACT3	ENST00000300875.4	c.584A>G	p.Lys195Arg	missense_variant	4/4	1		ENSP00000300875.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1139178 Hom.: 0 Cov.: 31 AF XY: 0.00000361 AC XY: 2 AN XY: 553854

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: 0.00000105

Gnomad4 OTH exome AF: 0.0000223

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

Jul 30, 2023

The c.1259A>G (p.K420R) alteration is located in exon 4 (coding exon 4) of the DACT3 gene. This alteration results from a A to G substitution at nucleotide position 1259, causing the lysine (K) at amino acid position 420 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.99	.;D
Vest4		0.074
MutPred		0.22		.;Loss of methylation at K420 (P = 0.0165);
MVP		0.51
ClinPred		0.59	D
GERP RS		2.7
Varity_R		0.13
gMVP		0.26

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: rs2052951214; hg19: chr19-47152370;