19-46660908-C-T

Variant names:

• chr19-46660908-C-T
• rs1408750422
• NM_145056.3:c.157G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145056.3(DACT3):​c.157G>A​(p.Gly53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,804 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

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]

DACT3-AS1 (HGNC:44120): (DACT3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34986043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT3	NM_145056.3	c.157G>A	p.Gly53Arg	missense_variant	Exon 1 of 4	ENST00000391916.7	NP_659493.2
DACT3-AS1	NR_040042.1	n.45+500C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DACT3	ENST00000391916.7	c.157G>A	p.Gly53Arg	missense_variant	Exon 1 of 4	5	NM_145056.3	ENSP00000375783.2
DACT3	ENST00000410105.2	c.157G>A	p.Gly53Arg	missense_variant	Exon 1 of 3	2		ENSP00000387300.1
DACT3-AS1	ENST00000525008.5	n.45+500C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000755 AC: 1 AN: 132480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385804 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 683892

Gnomad4 AFR exome AF: 0.0000321

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: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000532 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157G>A (p.G53R) alteration is located in exon 1 (coding exon 1) of the DACT3 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the glycine (G) at amino acid position 53 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	Pathogenic	0.73
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0078	T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Benign	0.088	T;D
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;D
Vest4		0.23
MutPred		0.26		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.47
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.13

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: rs1408750422; hg19: chr19-47164165;