19-46649134-C-T

Variant names:

• chr19-46649134-C-T
• rs928242049
• NM_145056.3:c.1238G>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.1238G>A​(p.Arg413His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,267,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R413C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• 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=0.20956871).

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.1238G>A	p.Arg413His	missense	Exon 4 of 4	NP_659493.2	Q96B18
	DACT3	NM_001301046.2		c.563G>A	p.Arg188His	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.1238G>A	p.Arg413His	missense	Exon 4 of 4	ENSP00000375783.2	Q96B18
	DACT3	ENST00000300875.4	TSL:1	c.563G>A	p.Arg188His	missense	Exon 4 of 4	ENSP00000300875.4	A0A0C4DFP1

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150742 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000627 AC: 7 AN: 1116710 Hom.: 0 Cov.: 31 AF XY: 0.00000740 AC XY: 4 AN XY: 540342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000226 AC: 5 AN: 22130

American (AMR) AF: 0.00 AC: 0 AN: 8454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13972

East Asian (EAS) AF: 0.00 AC: 0 AN: 24092

South Asian (SAS) AF: 0.00 AC: 0 AN: 36164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2888

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 941198

Other (OTH) AF: 0.0000228 AC: 1 AN: 43764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00762653), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150742 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73568

African (AFR) AF: 0.0000726 AC: 3 AN: 41324

American (AMR) AF: 0.0000661 AC: 1 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67460

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.042
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.14
MutPred		0.28		Loss of methylation at R413 (P = 0.0131)
MVP		0.49
ClinPred		0.76	D
GERP RS		2.7
Varity_R		0.16
gMVP		0.33
Mutation Taster		=94/6	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: rs928242049; hg19: chr19-47152391;