ZIC1

Zic family member 1, the group of Zinc fingers C2H2-type

Basic information

Region (hg38): 3:147393422-147510293

Links

ENSG00000152977 ∙ NCBI:7545 ∙ OMIM:600470 ∙ HGNC:12872 ∙ Uniprot:Q15915 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• craniosynostosis 6 (Definitive), mode of inheritance: AD
• structural brain anomalies with impaired intellectual development and craniosynostosis (Strong), mode of inheritance: AD
• craniosynostosis 6 (Strong), mode of inheritance: AD
• craniosynostosis 6 (Moderate), mode of inheritance: AD
• isolated plagiocephaly (Supportive), mode of inheritance: AD
• isolated brachycephaly (Supportive), mode of inheritance: AD
• isolated oxycephaly (Supportive), mode of inheritance: AD
• Dandy-Walker syndrome (Limited), mode of inheritance: AD
• craniosynostosis 6 (Strong), mode of inheritance: AD
• structural brain anomalies with impaired intellectual development and craniosynostosis (Limited), mode of inheritance: Unknown
• craniosynostosis 6 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Craniosynostosis 6; Structural brain anomalies with impaired intellectual development and craniosynostosis	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Neurologic	26340333; 30391508

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZIC1 gene.

• not provided (2 variants)
• Structural brain anomalies with impaired intellectual development and craniosynostosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZIC1 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				44	5	49
missense		3	46	7	1	57
nonsense	1	3	1			5
start loss						0
frameshift	1					1
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				7	4	11
Total	2	6	48	58	10

Variants in ZIC1

This is a list of pathogenic ClinVar variants found in the ZIC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-147395833-G-A			Likely benign (Jul 17, 2023)
3-147395835-C-T			Likely benign (Apr 09, 2023)
3-147395842-G-T			Likely benign (Sep 25, 2023)
3-147395914-G-A			Uncertain significance (Sep 11, 2023)
3-147395990-G-C		not specified	Uncertain significance (Dec 02, 2022)
3-147395993-T-C			Uncertain significance (Oct 22, 2023)
3-147396011-C-T		not specified	Uncertain significance (Jul 14, 2023)
3-147396034-G-C			Benign (Dec 28, 2023)
3-147396037-T-A			Uncertain significance (Oct 24, 2023)
3-147396047-C-T			Benign (Jun 28, 2023)
3-147396053-C-A			Uncertain significance (Apr 24, 2023)
3-147396058-T-C			Uncertain significance (Nov 24, 2022)
3-147396072-C-T			Likely benign (May 14, 2023)
3-147396081-C-T			Likely benign (Sep 26, 2022)
3-147396085-T-C			Uncertain significance (Aug 01, 2022)
3-147396086-G-T			Uncertain significance (Jan 01, 2023)
3-147396113-G-A		not specified	Uncertain significance (Oct 26, 2022)
3-147396186-G-A			Likely benign (Nov 24, 2022)
3-147396189-G-T		not specified	Uncertain significance (May 31, 2023)
3-147396206-C-T			Uncertain significance (Apr 04, 2022)
3-147396214-G-T		not specified	Uncertain significance (Sep 17, 2021)
3-147396229-G-C			Uncertain significance (Aug 17, 2023)
3-147396233-G-A			Likely benign (Mar 12, 2022)
3-147396245-C-G			Benign/Likely benign (Jan 18, 2024)
3-147396245-C-T			Uncertain significance (Feb 19, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZIC1	protein_coding	protein_coding	ENST00000282928	3	116872

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.934	0.0662	123380	0	1	123381	0.00000405

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.57	160	281	0.569	0.0000127	2935
Missense in Polyphen		57	128.05	0.44512		1389
Synonymous	-2.81	161	122	1.32	0.00000596	889
Loss of Function	3.09	1	13.0	0.0767	5.65e-7	138

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a transcriptional activator. Involved in neurogenesis. Plays important roles in the early stage of organogenesis of the CNS, as well as during dorsal spinal cord development and maturation of the cerebellum. Involved in the spatial distribution of mossy fiber (MF) neurons within the pontine gray nucleus (PGN). Plays a role in the regulation of MF axon pathway choice. Promotes MF migration towards ipsilaterally- located cerebellar territories. May have a role in shear flow mechanotransduction in osteocytes. Retains nuclear GLI1 and GLI3 in the cytoplasm. Binds to the minimal GLI-consensus sequence 5'- TGGGTGGTC-3' (By similarity). {ECO:0000250|UniProtKB:P46684}.
• Disease: DISEASE: Craniosynostosis 6 (CRS6) [MIM:616602]: A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:26340333}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neural Crest Differentiation;Differentiation of white and brown adipocyte (Consensus)

Recessive Scores

• pRec: 0.281

Intolerance Scores

• loftool: 0.0318
• rvis_EVS: -0.49
• rvis_percentile_EVS: 22.09

Haploinsufficiency Scores

• pHI: 0.822
• hipred: Y
• hipred_score: 0.837
• ghis: 0.716

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.995

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Zic1
• Phenotype: muscle phenotype; growth/size/body region 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); skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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)

Zebrafish Information Network

• Gene name: zic1
• Affected structure: optic fissure
• Phenotype tag: abnormal
• Phenotype quality: closure incomplete

Gene ontology

• Biological process: pattern specification process;central nervous system development;brain development;adult walking behavior;regulation of smoothened signaling pathway;spinal cord development;cell differentiation;positive regulation of protein import into nucleus;inner ear morphogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleus;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;metal ion binding