chr14-58646856-G-A

Position:

• chr14-58646856-G-A

Variant summary

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

The NM_001079520.2(DACT1):​c.2122G>A​(p.Glu708Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

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]

LINC01500 (HGNC:51166): (long intergenic non-protein coding RNA 1500)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACT1	NM_001079520.2	c.2122G>A	p.Glu708Lys	missense_variant	4/4	ENST00000395153.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACT1	ENST00000395153.8	c.2122G>A	p.Glu708Lys	missense_variant	4/4	5	NM_001079520.2
LINC01500	ENST00000648996.1	n.226G>A		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Townes-Brocks syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Apr 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.3	.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.11	T;D;D;T
Polyphen		0.99	.;.;D;.
Vest4		0.62
MutPred		0.25		.;.;Gain of ubiquitination at E745 (P = 0.0011);.;
MVP		0.55
MPC		0.60
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.61
gMVP		0.32

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: rs1285883896; hg19: chr14-59113574; COSMIC: COSV100242182; COSMIC: COSV100242182;