chr19-46648894-C-T

Variant names:

• chr19-46648894-C-T
• rs1235082797
• NM_145056.3:c.1478G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21198744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145056.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT3	NM_145056.3	MANE Select	c.1478G>A	p.Arg493Gln	missense	Exon 4 of 4	NP_659493.2	Q96B18
	DACT3	NM_001301046.2		c.803G>A	p.Arg268Gln	missense	Exon 4 of 4	NP_001287975.1	A0A0C4DFP1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT3	ENST00000391916.7	TSL:5 MANE Select	c.1478G>A	p.Arg493Gln	missense	Exon 4 of 4	ENSP00000375783.2	Q96B18
	DACT3	ENST00000300875.4	TSL:1	c.803G>A	p.Arg268Gln	missense	Exon 4 of 4	ENSP00000300875.4	A0A0C4DFP1

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

African (AFR) AF: 0.00 AC: 0 AN: 23458

American (AMR) AF: 0.00 AC: 0 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16880

East Asian (EAS) AF: 0.00 AC: 0 AN: 27574

South Asian (SAS) AF: 0.00 AC: 0 AN: 53566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3450

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 1001920

Other (OTH) AF: 0.00 AC: 0 AN: 49982

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.095
Sift	Uncertain	0.023	D
Sift4G	Benign	0.53	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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1235082797; hg19: chr19-47152151;