14-58645492-A-G

Variant summary

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

The NM_001079520.2(DACT1):c.758A>G(p.Asn253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00100

Genes affected

DACT1 (HGNC:17748): (dishevelled binding antagonist of beta catenin 1) The protein encoded by this gene belongs to the dapper family, characterized by the presence of PDZ-binding motif at the C-terminus. It interacts with, and positively regulates dishevelled-mediated signaling pathways during development. Depletion of this mRNA from xenopus embryos resulted in loss of notochord and head structures, and mice lacking this gene died shortly after birth from severe posterior malformations. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

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=0.06911695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACT1	NM_001079520.2	c.758A>G	p.Asn253Ser	missense_variant	4/4	ENST00000395153.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACT1	ENST00000395153.8	c.758A>G	p.Asn253Ser	missense_variant	4/4	5	NM_001079520.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Nov 13, 2023

The c.869A>G (p.N290S) alteration is located in exon 4 (coding exon 4) of the DACT1 gene. This alteration results from a A to G substitution at nucleotide position 869, causing the asparagine (N) at amino acid position 290 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.4
Dann	Benign	0.74
DEOGEN2	Benign	0.043	T;.;.;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.069	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.51	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;D;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.071
MutPred		0.29		.;.;.;Gain of phosphorylation at N290 (P = 0.0602);.;
MVP		0.34
MPC		0.14
ClinPred		0.084	T
GERP RS		-1.5
Varity_R		0.048
gMVP		0.058

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1475886511; hg19: chr14-59112210; COSMIC: COSV100242121; COSMIC: COSV100242121;