ZFHX3

protein-coding

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

Gene summary

This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Previous symbols:

ATBF1
C16orf47

MANE transcript

NM_006885.4

Inheritance

AR, AD

ClinVar variants

P:55U:701B:229

Top phenotype

Spinocerebellar ataxia 4

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr16:72,782,885-73,891,871

External References & Databases

Ensembl (ENSG00000140836)

Transcript & Mutation Effects

hg38 • Region Span ~1,109.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: PanelApp Australia

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

epilepsyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005027

Submitter: Ambry Genetics

syndromic complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: Broad Center for Mendelian Genomics

spinocerebellar ataxia type 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010847

Submitter: Ambry Genetics

spinocerebellar ataxia type 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010847

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 4AD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 38035881; 38684900; 38973251

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFHX3 variants in ClinVar

23 Conditions Cataloged

not specifiedTotal: 643

not providedTotal: 343

ZFHX3-related disorderTotal: 132

Neurodevelopmental disorderTotal: 10

Epilepsy, idiopathic generalized 20Total: 5

Spinocerebellar ataxia type 4Total: 2

Autism spectrum disorderTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006885.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	149 clinvar	11 clinvar	170
missense	2 clinvar	1 clinvar	645 clinvar	51 clinvar	18 clinvar	717
nonsense	13 clinvar	15 clinvar	13 clinvar			41
start loss						0
frameshift	8 clinvar	15 clinvar	30 clinvar			53
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	23	32	701	200	29	985

Highest pathogenic variant AF is 0.00006365627

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006885.4	RefSeq	NP_008816.3	9	MANE Select
ENST00000268489.10	Ensembl	ENSP00000268489.5	9	MANE Select
NM_001164766.2	RefSeq	NP_001158238.1	8	Standard
NM_001386735.1	RefSeq	NP_001373664.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

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

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

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268489
Coding exons: 9
Length: 276814
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.23	2279	2.12e+3	1.08	0.000128	24335
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00018	0.00016	rare
Finnish	0.00020	0.00018	rare
European (Non-Finnish)	0.00023	0.00021	rare
South Asian	0.00021	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.155

Intolerance Scores

LoFtool: 0.0860
RVIS EVS: -4.26
RVIS percentile EVS: 0.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.890

Gene Damage Prediction

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