14-58638386-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001079520.2(DACT1):c.184C>T(p.Arg62Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACT1	NM_001079520.2	c.184C>T	p.Arg62Cys	missense_variant	1/4	ENST00000395153.8
DACT1	NM_016651.6	c.184C>T	p.Arg62Cys	missense_variant	1/4
DACT1	NR_046093.2	n.126-2350C>T		intron_variant, non_coding_transcript_variant
DACT1	NR_165650.1	n.126-2350C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACT1	ENST00000395153.8	c.184C>T	p.Arg62Cys	missense_variant	1/4	5	NM_001079520.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1147946 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 551138

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 13, 2023

The c.184C>T (p.R62C) alteration is located in exon 1 (coding exon 1) of the DACT1 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the arginine (R) at amino acid position 62 to be replaced by a cysteine (C). 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	0.85
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.55
MutPred		0.45		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);
MVP		0.71
MPC		4.3
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.76
gMVP		0.45

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: rs2047594056; hg19: chr14-59105104;