14-58646014-C-G

Variant names:

• chr14-58646014-C-G
• rs17832998
• NM_001079520.2:c.1280C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079520.2(DACT1):​c.1280C>G​(p.Ala427Gly) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A427V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• Publications: 29 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06944206).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079520.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT1	NM_001079520.2	MANE Select	c.1280C>G	p.Ala427Gly	missense	Exon 4 of 4	NP_001072988.1	Q9NYF0-2
	DACT1	NM_016651.6		c.1391C>G	p.Ala464Gly	missense	Exon 4 of 4	NP_057735.2
	DACT1	NR_046093.2		n.1060C>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT1	ENST00000395153.8	TSL:5 MANE Select	c.1280C>G	p.Ala427Gly	missense	Exon 4 of 4	ENSP00000378582.3	Q9NYF0-2
	DACT1	ENST00000335867.4	TSL:1	c.1391C>G	p.Ala464Gly	missense	Exon 4 of 4	ENSP00000337439.4	Q9NYF0-1
	DACT1	ENST00000707126.1		c.1280C>G	p.Ala427Gly	missense	Exon 4 of 4	ENSP00000516754.1	Q9NYF0-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250366 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.3
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.079
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.030
Sift	Benign	0.066	T
Sift4G	Benign	0.23	T
Polyphen		0.015	B
Vest4		0.089
MutPred		0.077		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.37
MPC		0.19
ClinPred		0.037	T
GERP RS		2.4
Varity_R		0.079
gMVP		0.14
Mutation Taster		=95/5	polymorphism

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: rs17832998; hg19: chr14-59112732;