ZFHX3

zinc finger homeobox 3, the group of Zinc fingers C2H2-type|ZF class homeoboxes and pseudogenes

Basic information

Region (hg38): 16:72782885-73891871

Previous symbols: [ "ATBF1", "C16orf47" ]

Links

ENSG00000140836 ∙ NCBI:463 ∙ OMIM:104155 ∙ HGNC:777 ∙ Uniprot:Q15911 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• epilepsy (Limited), mode of inheritance: AR
• spinocerebellar ataxia type 4 (Moderate), mode of inheritance: AD
• syndromic complex neurodevelopmental disorder (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia 4	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	Neurologic	38035881; 38684900; 38973251

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZFHX3 gene.

• not specified (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZFHX3 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			3	30	13	46
missense			301	15	13	329
nonsense	2	6	4			12
start loss						0
frameshift		1	17			18
inframe indel			4	2	8	14
splice donor/acceptor (+/-2bp)						0
splice region			1		1	2
non coding						0
Total	2	7	329	47	34

Variants in ZFHX3

This is a list of pathogenic ClinVar variants found in the ZFHX3 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-72787197-C-CA			Uncertain significance (Jul 20, 2022)
16-72787220-T-C		not specified	Uncertain significance (Mar 30, 2024)
16-72787224-G-C		not specified	Uncertain significance (Mar 30, 2024)
16-72787228-T-C		not specified	Uncertain significance (Mar 30, 2024)
16-72787228-T-G		not specified	Uncertain significance (Aug 02, 2021)
16-72787229-T-G		not specified	Uncertain significance (Mar 30, 2024)
16-72787240-A-G		not specified	Uncertain significance (Mar 30, 2024)
16-72787301-C-T		not specified	Uncertain significance (Jan 30, 2024)
16-72787302-G-A			Likely benign (May 01, 2022)
16-72787338-G-C		not specified	Uncertain significance (Sep 11, 2024)
16-72787346-T-G		not specified	Uncertain significance (Apr 24, 2024)
16-72787355-C-T		not specified	Uncertain significance (Jul 06, 2021)
16-72787369-G-A		not specified	Uncertain significance (Nov 10, 2024)
16-72787387-G-A		not specified	Uncertain significance (Oct 01, 2024)
16-72787391-G-A		not specified	Uncertain significance (Jun 02, 2024)
16-72787396-G-C		not specified	Uncertain significance (Mar 30, 2024)
16-72787400-C-G		not specified	Uncertain significance (Mar 30, 2024)
16-72787403-A-G		not specified	Uncertain significance (Mar 30, 2024)
16-72787404-A-G		ZFHX3-related disorder	Benign (Oct 01, 2022)
16-72787412-A-G		not specified	Uncertain significance (Mar 30, 2024)
16-72787423-G-A		not specified	Uncertain significance (Jul 12, 2023)
16-72787435-C-G		not specified	Uncertain significance (Sep 20, 2023)
16-72787444-T-A		not specified	Uncertain significance (Aug 08, 2023)
16-72787445-G-A		ZFHX3-related disorder	Benign (Dec 31, 2019)
16-72787446-G-C		ZFHX3-related disorder	Benign (Nov 16, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZFHX3	protein_coding	protein_coding	ENST00000268489	9	276814

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.39e-13	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.23	2279	2.12e+3	1.08	0.000128	24335
Missense in Polyphen		553	640.33	0.86362		7621
Synonymous	-6.30	1171	927	1.26	0.0000650	7409
Loss of Function	9.52	10	125	0.0801	0.00000673	1418

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000218	0.000214
Ashkenazi Jewish	0.000204	0.000198
East Asian	0.000184	0.000163
Finnish	0.000198	0.000185
European (Non-Finnish)	0.000226	0.000211
Middle Eastern	0.000184	0.000163
South Asian	0.000206	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional regulator which can act as an activator or a repressor. Inhibits the enhancer element of the AFP gene by binding to its AT-rich core sequence. In concert with SMAD- dependent TGF-beta signaling can repress the transcription of AFP via its interaction with SMAD2/3 (PubMed:25105025). Regulates the circadian locomotor rhythms via transcriptional activation of neuropeptidergic genes which are essential for intercellular synchrony and rhythm amplitude in the suprachiasmatic nucleus (SCN) of the brain (By similarity). Regulator of myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter and promoter repression (PubMed:11312261). Down- regulates the MUC5AC promoter in gastric cancer (PubMed:17330845). In association with RUNX3, upregulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). Inhibits estrogen receptor (ESR1) function by selectively competing with coactivator NCOA3 for binding to ESR1 in ESR1-positive breast cancer cells (PubMed:20720010). {ECO:0000250|UniProtKB:Q61329, ECO:0000269|PubMed:11312261, ECO:0000269|PubMed:17330845, ECO:0000269|PubMed:20599712, ECO:0000269|PubMed:20720010, ECO:0000269|PubMed:25105025}.
• Pathway: Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);fibrinolysis pathway;intrinsic prothrombin activation pathway;C-MYB transcription factor network;extrinsic prothrombin activation pathway (Consensus)

Recessive Scores

• pRec: 0.155

Intolerance Scores

• loftool: 0.0860
• rvis_EVS: -4.26
• rvis_percentile_EVS: 0.12

Haploinsufficiency Scores

• pHI: 0.746
• hipred: Y
• hipred_score: 0.595
• ghis: 0.603

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.890

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Zfhx3
• Phenotype: neoplasm; reproductive system 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; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); renal/urinary system 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); growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;regulation of transcription, DNA-templated;transcription by RNA polymerase II;brain development;muscle organ development;circadian regulation of gene expression;regulation of neuron differentiation;positive regulation of cell adhesion;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;response to transforming growth factor beta;regulation of locomotor rhythm
• Cellular component: nucleus;nucleoplasm;transcription factor complex;cytoplasm;nuclear body
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;protein binding;zinc ion binding;enzyme binding;transcription regulatory region DNA binding