19-46648894-C-T

Variant names:

• chr19-46648894-C-T
• NM_145056.3:c.1478G>A

Variant summary

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

The NM_145056.3(DACT3):​c.1478G>A​(p.Arg493Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 1,216,672 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R493P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08

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=0.21198744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT3	NM_145056.3	c.1478G>A	p.Arg493Gln	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.1478G>A	p.Arg493Gln	missense_variant	Exon 4 of 4	5	NM_145056.3	ENSP00000375783.2
DACT3	ENST00000300875.4	c.803G>A	p.Arg268Gln	missense_variant	Exon 4 of 4	1		ENSP00000300875.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000164 AC: 2 AN: 1216672 Hom.: 0 Cov.: 31 AF XY: 0.00000169 AC XY: 1 AN XY: 591510

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: 0.00000200

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.095
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.53	T;T
Polyphen		0.092	.;B
Vest4		0.042
MutPred		0.40		.;Loss of methylation at R493 (P = 0.0067);
MVP		0.42
ClinPred		0.19	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-47152151;