14-58646633-G-T

Position:

• chr14-58646633-G-T

Variant summary

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

The NM_001079520.2(DACT1):​c.1899G>T​(p.Lys633Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3423906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACT1	NM_001079520.2	c.1899G>T	p.Lys633Asn	missense_variant	4/4	ENST00000395153.8	NP_001072988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DACT1	ENST00000395153.8	c.1899G>T	p.Lys633Asn	missense_variant	4/4	5	NM_001079520.2	ENSP00000378582
LINC01500	ENST00000648996.1	n.3G>T		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458816 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 725580

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T;.;T;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.0	.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.4	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.035	D;T;T;D
Polyphen		0.98	.;.;D;.
Vest4		0.46
MutPred		0.25		.;.;Loss of methylation at K670 (P = 0.006);.;
MVP		0.56
MPC		0.72
ClinPred		0.81	D
GERP RS		2.2
Varity_R		0.42
gMVP		0.36

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: rs754847137; hg19: chr14-59113351;