DACT1

dishevelled binding antagonist of beta catenin 1, the group of dishevelled binding antagonist of beta catenin family

Basic information

Region (hg38): 14:58633966-58648321

Links

ENSG00000165617 ∙ NCBI:51339 ∙ OMIM:607861 ∙ HGNC:17748 ∙ Uniprot:Q9NYF0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Townes-Brocks syndrome (Supportive), mode of inheritance: AD
• Townes-Brocks syndrome 2 (Limited), mode of inheritance: AD
• Townes-Brocks syndrome 2 (Limited), mode of inheritance: AD
• Townes-Brocks syndrome 2 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Townes-Brocks syndrome 2	AD	Renal	Individuals have been described with manifestations including vesicoureteral reflux, and surveillance and management may be helpful to preserve renal function	Craniofacial; Gastrointestinal; Genitourinary; Neurologic; Renal	28054444; 36066768

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DACT1 gene.

• Inborn genetic diseases (48 variants)
• not provided (38 variants)
• Townes-Brocks syndrome 2 (7 variants)
• DACT1-related condition (3 variants)
• Rieger anomaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DACT1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				12	9	21
missense			52	9	5	66
nonsense						0
start loss						0
frameshift		1				1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1	1	2
Total	0	1	52	22	15

Variants in DACT1

This is a list of pathogenic ClinVar variants found in the DACT1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-58638221-G-C		not specified	Uncertain significance (Oct 16, 2023)
14-58638227-G-C		DACT1-related disorder	Uncertain significance (Sep 13, 2023)
14-58638326-C-A		not specified	Uncertain significance (May 27, 2022)
14-58638349-G-A			Likely benign (Jun 20, 2018)
14-58638358-G-A			Likely benign (Dec 31, 2019)
14-58638386-C-T		not specified	Uncertain significance (Dec 13, 2023)
14-58638439-G-C			Benign (Dec 26, 2018)
14-58638453-C-T			Likely benign (Sep 14, 2018)
14-58638455-C-G		not specified	Uncertain significance (Feb 14, 2023)
14-58638462-G-T		DACT1-related disorder	Benign/Likely benign (Dec 31, 2019)
14-58638470-C-T		Townes-Brocks syndrome 2	Benign (Jul 30, 2021)
14-58638508-G-A			Likely benign (Feb 22, 2018)
14-58640877-T-G		DACT1-related disorder	Benign/Likely benign (Dec 29, 2022)
14-58641695-C-T			Likely benign (Aug 09, 2017)
14-58641734-C-T		DACT1-related disorder	Likely benign (Feb 14, 2020)
14-58641737-C-G			Likely benign (May 24, 2018)
14-58641744-G-T		not specified	Uncertain significance (Nov 09, 2021)
14-58645248-T-C			Likely benign (Nov 15, 2018)
14-58645315-C-A		not specified	Uncertain significance (Sep 14, 2022)
14-58645324-G-A		not specified	Uncertain significance (Aug 01, 2022)
14-58645342-A-G		not specified	Uncertain significance (Apr 12, 2023)
14-58645363-T-C		not specified	Uncertain significance (Dec 01, 2022)
14-58645437-C-T		not specified	Uncertain significance (Jul 14, 2022)
14-58645486-C-T		not specified	Uncertain significance (Aug 10, 2023)
14-58645492-A-G		not specified	Uncertain significance (Nov 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DACT1	protein_coding	protein_coding	ENST00000335867	4	14355

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.400	0.600	125739	0	9	125748	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.527	487	455	1.07	0.0000283	5343
Missense in Polyphen		183	198.85	0.92027		2500
Synonymous	-0.699	227	214	1.06	0.0000157	1748
Loss of Function	3.42	5	22.5	0.222	0.00000112	307

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000811	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in regulation of intracellular signaling pathways during development. Specifically thought to play a role in canonical and/or non-canonical Wnt signaling pathways through interaction with DSH (Dishevelled) family proteins. The activation/inhibition of Wnt signaling may depend on the phosphorylation status. Proposed to regulate the degradation of CTNNB1/beta-catenin, thereby modulating the transcriptional activation of target genes of the Wnt signaling pathway. Its function in stabilizing CTNNB1 may involve inhibition of GSK3B activity. Promotes the membrane localization of CTNNB1. The cytoplasmic form can induce DVL2 degradation via a lysosome- dependent mechanism; the function is inhibited by PKA-induced binding to 14-3-3 proteins, such as YWHAB. Seems to be involved in morphogenesis at the primitive streak by regulating VANGL2 and DVL2; the function seems to be independent of canonical Wnt signaling and rather involves the non-canonical Wnt/planar cell polarity (PCP) pathway (By similarity). The nuclear form may prevent the formation of LEF1:CTNNB1 complex and recruit HDAC1 to LEF1 at target gene promoters to repress transcription thus antagonizing Wnt signaling. May be involved in positive regulation of fat cell differentiation. During neuronal differentiation may be involved in excitatory synapse organization, and dendrite formation and establishment of spines. {ECO:0000250, ECO:0000269|PubMed:15580286, ECO:0000269|PubMed:16446366, ECO:0000269|PubMed:17197390, ECO:0000269|PubMed:18936100, ECO:0000269|PubMed:22470507}.
• Disease: DISEASE: Neural tube defects (NTD) [MIM:182940]: Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. {ECO:0000269|PubMed:22610794}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Townes-Brocks syndrome 2 (TBS2) [MIM:617466]: A form of Townes-Brocks syndrome, a rare autosomal dominant disease characterized by the triad of imperforate anus, dysplastic ears, and thumb malformations. Minor features of the condition include hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. {ECO:0000269|PubMed:28054444}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling by WNT;Signal Transduction;Degradation of DVL;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.125

Intolerance Scores

• loftool: 0.244
• rvis_EVS: 0.2
• rvis_percentile_EVS: 67.43

Haploinsufficiency Scores

• pHI: 0.152
• hipred: Y
• hipred_score: 0.853
• ghis: 0.503

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.525

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Dact1
• Phenotype: embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: dact1
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;Wnt signaling pathway;neural tube development;regulation of Wnt signaling pathway;positive regulation of Wnt signaling pathway;negative regulation of Wnt signaling pathway;regulation of protein stability;negative regulation of protein binding;positive regulation of protein binding;positive regulation of protein catabolic process;negative regulation of JNK cascade;embryonic hindgut morphogenesis;regulation of canonical Wnt signaling pathway;negative regulation of canonical Wnt signaling pathway;positive regulation of canonical Wnt signaling pathway;regulation of nodal signaling pathway;positive regulation of cellular protein catabolic process;negative regulation of beta-catenin-TCF complex assembly;regulation of Wnt signaling pathway, planar cell polarity pathway;negative regulation of G1/S transition of mitotic cell cycle
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;cell junction;beta-catenin destruction complex;synapse
• Molecular function: RNA polymerase II transcription factor binding;protein kinase C binding;protein binding;beta-catenin binding;histone deacetylase binding;protein kinase A binding;delta-catenin binding