14-58646712-G-A

Position:

• chr14-58646712-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079520.2(DACT1):​c.1978G>A​(p.Gly660Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,612,976 control chromosomes in the GnomAD database, including 35,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5527 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30335 hom.)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032674968).
• BP6: Variant 14-58646712-G-A is Benign according to our data. Variant chr14-58646712-G-A is described in ClinVar as [Benign]. Clinvar id is 1257885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACT1	NM_001079520.2	c.1978G>A	p.Gly660Ser	missense_variant	4/4	ENST00000395153.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACT1	ENST00000395153.8	c.1978G>A	p.Gly660Ser	missense_variant	4/4	5	NM_001079520.2
LINC01500	ENST00000648996.1	n.82G>A		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38374 AN: 151982 Hom.: 5512 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.230 AC: 56667 AN: 246124 Hom.: 7358 AF XY: 0.222 AC XY: 29837 AN XY: 134168

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.197 AC: 287951 AN: 1460876 Hom.: 30335 Cov.: 38 AF XY: 0.197 AC XY: 143174 AN XY: 726790

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.253 AC: 38427 AN: 152100 Hom.: 5527 Cov.: 32 AF XY: 0.250 AC XY: 18613 AN XY: 74374

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.257

Alfa AF: 0.212 Hom.: 2998

Bravo AF: 0.269

TwinsUK AF: 0.180 AC: 667

ALSPAC AF: 0.177 AC: 684

ESP6500AA AF: 0.358 AC: 1574

ESP6500EA AF: 0.191 AC: 1642

ExAC AF: 0.227 AC: 27491

Asia WGS AF: 0.195 AC: 676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2019	- -

DACT1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.8
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.69	.;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;.;M;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.049
MPC		0.18
ClinPred		0.0034	T
GERP RS		0.84
Varity_R		0.034
gMVP		0.16

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: rs698025; hg19: chr14-59113430; COSMIC: COSV60019635; COSMIC: COSV60019635;