ZC4H2

zinc finger C4H2-type containing, the group of Zinc fingers

Basic information

Region (hg38): X:64915802-65034713

Previous symbols: [ "KIAA1166", "WWS", "MCS", "MRXS4" ]

Links

ENSG00000126970 ∙ NCBI:55906 ∙ OMIM:300897 ∙ HGNC:24931 ∙ Uniprot:Q9NQZ6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wieacker-Wolff syndrome (Definitive), mode of inheritance: XLR
• Wieacker-Wolff syndrome (Definitive), mode of inheritance: XLD
• Wieacker-Wolff syndrome (Strong), mode of inheritance: XL
• Wieacker-Wolff syndrome (Supportive), mode of inheritance: XL
• Wieacker-Wolff syndrome (Definitive), mode of inheritance: XL
• Wieacker-Wolff syndrome (Definitive), mode of inheritance: XL
• Wieacker-Wolff syndrome, female-restricted (Definitive), mode of inheritance: XL
• X-linked syndromic intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Wieacker-Wolff syndrome; Wieacker-Wolff syndrome, female-restricted	XL	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; Genitourinary; Musculoskeletal; Neurologic	23623388; 26056227; 28345801; 31206972

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZC4H2 gene.

• not provided (11 variants)
• Wieacker-Wolff syndrome (7 variants)
• Inborn genetic diseases (5 variants)
• Wieacker-Wolff syndrome, female-restricted (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZC4H2 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				19	5	24
missense	4	8	47	4		63
nonsense	3	4				7
start loss	1		1			2
frameshift	8	2	1			11
inframe indel		1	3			4
splice donor/acceptor (+/-2bp)		1				1
splice region	2	3	1	1		7
non coding		1	1	14	6	22
Total	16	17	53	37	11

Variants in ZC4H2

This is a list of pathogenic ClinVar variants found in the ZC4H2 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-64917774-T-C			Uncertain significance (Oct 07, 2019)
X-64917800-G-A			Uncertain significance (Sep 23, 2021)
X-64917804-C-T		Inborn genetic diseases	Benign (Dec 19, 2023)
X-64917805-G-A		Inborn genetic diseases	Uncertain significance (Oct 27, 2023)
X-64917808-T-C		Wieacker-Wolff syndrome	Pathogenic (Apr 09, 2020)
X-64917820-C-T			Conflicting classifications of pathogenicity (Nov 13, 2023)
X-64917821-G-A		Wieacker-Wolff syndrome • Inborn genetic diseases	Pathogenic (Feb 14, 2022)
X-64917827-G-A		Wieacker-Wolff syndrome • ZC4H2-related disorder	Likely pathogenic (Aug 05, 2022)
X-64917831-C-G			Pathogenic (Sep 20, 2021)
X-64917839-T-G			Uncertain significance (Sep 01, 2019)
X-64917840-G-T			Likely pathogenic (May 19, 2021)
X-64917841-C-A		Wieacker-Wolff syndrome, female-restricted	Likely pathogenic (Oct 05, 2016)
X-64917843-A-G			Likely benign (Aug 10, 2023)
X-64917843-A-T		Inborn genetic diseases	Benign (Feb 01, 2024)
X-64917845-G-C			Uncertain significance (Jul 08, 2020)
X-64917850-C-A			Likely pathogenic (Sep 09, 2015)
X-64917857-G-A		Wieacker-Wolff syndrome • Neurodevelopmental disorder	Likely pathogenic (Jun 24, 2020)
X-64917860-C-T		Wieacker-Wolff syndrome	Pathogenic (Mar 23, 2020)
X-64917865-C-T		Wieacker-Wolff syndrome • Wieacker-Wolff syndrome, female-restricted	Pathogenic (May 27, 2023)
X-64917866-G-A		Wieacker-Wolff syndrome • Wieacker-Wolff syndrome, female-restricted;Wieacker-Wolff syndrome	Pathogenic/Likely pathogenic (Jun 26, 2023)
X-64917866-G-C		Wieacker-Wolff syndrome, female-restricted	Likely pathogenic (Jan 01, 2022)
X-64917866-G-T		Inborn genetic diseases • ZC4H2-related disorder	Benign (Jan 08, 2024)
X-64917867-G-T			Uncertain significance (Sep 08, 2022)
X-64917871-A-T			Uncertain significance (Jul 03, 2019)
X-64917881-GA-G		Wieacker-Wolff syndrome	Pathogenic (Jan 28, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZC4H2	protein_coding	protein_coding	ENST00000374839	5	118344

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.908	0.0918	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.51	47	86.6	0.543	0.00000694	1487
Missense in Polyphen		10	30.128	0.33192		481
Synonymous	-1.42	43	32.7	1.32	0.00000251	405
Loss of Function	2.57	0	7.68	0.00	5.54e-7	139

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)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role in interneurons differentiation (PubMed:26056227). Involved in neuronal development and in neuromuscular junction formation. {ECO:0000269|PubMed:23623388, ECO:0000269|PubMed:26056227}.

Recessive Scores

• pRec: 0.113

Intolerance Scores

• loftool: 0.0870
• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.4

Haploinsufficiency Scores

• pHI: 0.245
• hipred: Y
• hipred_score: 0.505
• ghis: 0.636

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Zc4h2

Zebrafish Information Network

• Gene name: zc4h2
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: nervous system development;neuromuscular junction development;spinal cord motor neuron differentiation;positive regulation of neuron differentiation
• Cellular component: nucleus;cytoplasm;cell junction;postsynaptic membrane
• Molecular function: protein binding;metal ion binding