chr14-58645757-C-T

Variant names:

• chr14-58645757-C-T
• rs863091
• NM_001079520.2:c.1023C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001079520.2(DACT1):​c.1023C>T​(p.Val341Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,614,080 control chromosomes in the GnomAD database, including 35,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5561 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30027 hom.)
• Consequence: DACT1 NM_001079520.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.103
• Publications: 20 publications found

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]

DACT1 Gene-Disease associations (from GenCC):

• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Townes-Brocks syndrome 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-58645757-C-T is Benign according to our data. Variant chr14-58645757-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059824.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACT1	NM_001079520.2	c.1023C>T	p.Val341Val	synonymous_variant	Exon 4 of 4	ENST00000395153.8	NP_001072988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DACT1	ENST00000395153.8	c.1023C>T	p.Val341Val	synonymous_variant	Exon 4 of 4	5	NM_001079520.2	ENSP00000378582.3

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38367 AN: 152112 Hom.: 5545 Cov.: 33

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.228 AC: 57268 AN: 251298 AF XY: 0.220

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.196 AC: 287154 AN: 1461850 Hom.: 30027 Cov.: 34 AF XY: 0.196 AC XY: 142702 AN XY: 727230

African (AFR) AF: 0.389 AC: 13036 AN: 33478

American (AMR) AF: 0.354 AC: 15851 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6364 AN: 26136

East Asian (EAS) AF: 0.133 AC: 5278 AN: 39696

South Asian (SAS) AF: 0.208 AC: 17939 AN: 86252

European-Finnish (FIN) AF: 0.181 AC: 9652 AN: 53418

Middle Eastern (MID) AF: 0.276 AC: 1594 AN: 5768

European-Non Finnish (NFE) AF: 0.184 AC: 204643 AN: 1111992

Other (OTH) AF: 0.212 AC: 12797 AN: 60394

GnomAD4 genome AF: 0.252 AC: 38427 AN: 152230 Hom.: 5561 Cov.: 33 AF XY: 0.250 AC XY: 18633 AN XY: 74422

African (AFR) AF: 0.382 AC: 15854 AN: 41524

American (AMR) AF: 0.298 AC: 4559 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 827 AN: 3472

East Asian (EAS) AF: 0.142 AC: 734 AN: 5176

South Asian (SAS) AF: 0.200 AC: 964 AN: 4820

European-Finnish (FIN) AF: 0.168 AC: 1787 AN: 10608

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12951 AN: 68012

Other (OTH) AF: 0.256 AC: 541 AN: 2116

Alfa AF: 0.221 Hom.: 13347

Bravo AF: 0.269

Asia WGS AF: 0.196 AC: 680 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DACT1-related disorder Benign:1

Nov 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.7
DANN	Benign	0.82
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs863091; hg19: chr14-59112475; COSMIC: COSV60020988; COSMIC: COSV60020988;