ZIC3

Zic family member 3, the group of Zinc fingers C2H2-type

Basic information

Region (hg38): X:137566127-137577691

Previous symbols: [ "HTX1" ]

Links

ENSG00000156925 ∙ NCBI:7547 ∙ OMIM:300265 ∙ HGNC:12874 ∙ Uniprot:O60481 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• VACTERL association, X-linked, with or without hydrocephalus (Definitive), mode of inheritance: XLR
• VACTERL association, X-linked, with or without hydrocephalus (Strong), mode of inheritance: XL
• heterotaxy, visceral, 1, X-linked (Definitive), mode of inheritance: XLR
• heterotaxy, visceral, 1, X-linked (Moderate), mode of inheritance: XL
• VACTERL association, X-linked, with or without hydrocephalus (Moderate), mode of inheritance: XL
• VACTERL association, X-linked, with or without hydrocephalus (Definitive), mode of inheritance: XL
• heterotaxy, visceral, 1, X-linked (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital heart defects, nonsyndromic, 1, X-linked; Heterotaxy, visceral, 1, X-linked; VACTERL association, X-linked, with or without hydrocephalus	XL	Cardiovascular	The conditions can include congenital cardiac anomalies, and awareness may allow early identification and management	Cardiovascular; Genitourinary; Gastrointestinal; Musculoskeletal; Neurologic; Pulmonary; Renal	3674105; 9354794; 10980576; 14681828; 17295247; 20452998; 21465648; 21864452; 23427188; 24123890

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZIC3 gene.

• Heterotaxy, visceral, 1, X-linked (14 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZIC3 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			2	15	4	21
missense	1	3	37	8	1	50
nonsense	4	1				5
start loss						0
frameshift	10	3	1			14
inframe indel		1	2	3		6
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			13	5	2	20
Total	15	8	55	31	7

Variants in ZIC3

This is a list of pathogenic ClinVar variants found in the ZIC3 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-137566213-C-T		Heterotaxy, visceral, 1, X-linked • Congenital heart defects 1, nonsyndromic, 1 • VACTERL association, X-linked, with or without hydrocephalus	Uncertain significance (Jan 12, 2018)
X-137566268-C-A		Heterotaxy, visceral, 1, X-linked • VACTERL association, X-linked, with or without hydrocephalus	Uncertain significance (Jan 13, 2018)
X-137566357-C-T		Heterotaxy, visceral, 1, X-linked • VACTERL association, X-linked, with or without hydrocephalus	Uncertain significance (Jan 13, 2018)
X-137566523-A-C		Heterotaxy, visceral, 1, X-linked • VACTERL association, X-linked, with or without hydrocephalus	Uncertain significance (Jan 13, 2018)
X-137566709-C-T		Heterotaxy, visceral, 1, X-linked	Likely benign (Aug 23, 2022)
X-137566710-G-C		Heterotaxy, visceral, 1, X-linked	Conflicting classifications of pathogenicity (Mar 26, 2021)
X-137566717-C-G		Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
X-137566722-T-C			Uncertain significance (Dec 13, 2022)
X-137566727-T-C		Heterotaxy, visceral, 1, X-linked	Likely benign (Nov 28, 2023)
X-137566740-G-T		Heterotaxy, visceral, 1, X-linked • VACTERL association, X-linked, with or without hydrocephalus • not specified • Congenital heart defects 1, nonsyndromic, 1	Benign/Likely benign (Jul 01, 2024)
X-137566745-C-T		Heterotaxy, visceral, 1, X-linked	Likely benign (May 06, 2022)
X-137566766-C-G		Inborn genetic diseases	Uncertain significance (Jan 03, 2017)
X-137566767-G-C		VACTERL association, X-linked, with or without hydrocephalus	Uncertain significance (-)
X-137566771-T-C		ZIC3-related disorder	Uncertain significance (Apr 17, 2024)
X-137566783-A-T		Heterotaxy, visceral, 1, X-linked	Uncertain significance (Nov 08, 2019)
X-137566788-G-T		Heterotaxy, visceral, 1, X-linked • Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
X-137566789-C-T		Heterotaxy, visceral, 1, X-linked	Likely benign (Jul 17, 2023)
X-137566796-G-A		Heterotaxy, visceral, 1, X-linked	Uncertain significance (Jul 21, 2018)
X-137566799-GCTGA-G		Heterotaxy, visceral, 1, X-linked	Pathogenic (Jan 12, 2023)
X-137566807-C-T		VACTERL association, X-linked, with or without hydrocephalus • Heterotaxy, visceral, 1, X-linked	Uncertain significance (Jan 12, 2018)
X-137566819-C-A		Heterotaxy, visceral, 1, X-linked	Pathogenic (May 28, 2018)
X-137566819-C-G		Heterotaxy, visceral, 1, X-linked	Pathogenic (Nov 27, 2019)
X-137566822-C-G		Congenital heart defects 1, nonsyndromic, 1 • VACTERL association, X-linked, with or without hydrocephalus • Heterotaxy, visceral, 1, X-linked	Conflicting classifications of pathogenicity (Jan 12, 2018)
X-137566825-ACGC-A		Heterotaxy, visceral, 1, X-linked • ZIC3-related disorder	Conflicting classifications of pathogenicity (May 28, 2019)
X-137566825-ACGCCGC-A		Heterotaxy, visceral, 1, X-linked	Uncertain significance (Sep 10, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZIC3	protein_coding	protein_coding	ENST00000287538	3	11550

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.925	0.0747	125744	1	1	125746	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.52	94	192	0.489	0.0000128	3068
Missense in Polyphen		25	71.619	0.34907		1104
Synonymous	0.917	72	82.6	0.872	0.00000578	937
Loss of Function	2.67	0	8.28	0.00	5.28e-7	147

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000366	0.0000366
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000122	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. {ECO:0000269|PubMed:17764085}.
• Disease: DISEASE: Heterotaxy, visceral, 1, X-linked (HTX1) [MIM:306955]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. {ECO:0000269|PubMed:14681828, ECO:0000269|PubMed:17295247, ECO:0000269|PubMed:17764085, ECO:0000269|PubMed:18716025, ECO:0000269|PubMed:24123890, ECO:0000269|PubMed:9354794}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: VACTERL association X-linked with or without hydrocephalus (VACTERLX) [MIM:314390]: A syndrome characterized by a non-random association of congenital defects. Affected individuals manifest vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula (TE), renal anomalies (R) such as urethral atresia with hydronephrosis, and limb anomalies (L) such as hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb. Some patients may have hydrocephalus. Some cases of VACTERL-H are associated with increased chromosome breakage and rearrangement. {ECO:0000269|PubMed:20452998, ECO:0000269|PubMed:24123890}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital heart defects, multiple types, 1, X-linked (CHTD1) [MIM:306955]: A disorder characterized by congenital developmental abnormalities involving structures of the heart. Common defects include transposition of the great arteries, aortic stenosis, atrial septal defect, ventricular septal defect, pulmonic stenosis, and patent ductus arteriosus. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions. {ECO:0000269|PubMed:14681828, ECO:0000269|PubMed:17764085, ECO:0000269|PubMed:24123890}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Mesodermal Commitment Pathway;POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation;Developmental Biology;POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation;Transcriptional regulation of pluripotent stem cells (Consensus)

Recessive Scores

• pRec: 0.168

Intolerance Scores

• rvis_EVS: 0.61
• rvis_percentile_EVS: 83.07

Haploinsufficiency Scores

• pHI: 0.888
• hipred: Y
• hipred_score: 0.735

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Zic3
• Phenotype: growth/size/body region phenotype; cellular phenotype; craniofacial phenotype; hearing/vestibular/ear 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); limbs/digits/tail phenotype; digestive/alimentary 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); normal phenotype; reproductive system phenotype; hematopoietic 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: zic3
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: increased curvature

Gene ontology

• Biological process: heart looping;determination of left/right symmetry;central nervous system development;anterior/posterior pattern specification;cell differentiation;lung development;somatic stem cell population maintenance;determination of pancreatic left/right asymmetry;determination of left/right asymmetry in nervous system;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;determination of digestive tract left/right asymmetry;determination of liver left/right asymmetry
• Cellular component: nucleus;nucleoplasm;cytoplasm
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;protein binding;sequence-specific DNA binding;metal ion binding