GRHL3

grainyhead like transcription factor 3

Basic information

Region (hg38): 1:24199557-24364482

Previous symbols: [ "TFCP2L4" ]

Links

ENSG00000158055 ∙ NCBI:57822 ∙ OMIM:608317 ∙ HGNC:25839 ∙ Uniprot:Q8TE85 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• van der Woude syndrome 1 (Definitive), mode of inheritance: AD
• van der Woude syndrome 2 (Strong), mode of inheritance: AD
• van der Woude syndrome (Supportive), mode of inheritance: AD
• van der Woude syndrome 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
van der Woude syndrome 2	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; Dental; Musculoskeletal	24360809

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRHL3 gene.

• not provided (50 variants)
• Van der Woude syndrome 2 (42 variants)
• Inborn genetic diseases (21 variants)
• Isolated cleft palate (6 variants)
• GRHL3-related condition (5 variants)
• not specified (2 variants)
• Van der Woude syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRHL3 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		1	1	7	7	16
missense		2	30	2	9	43
nonsense	1					1
start loss			1			1
frameshift	1	1				2
inframe indel						0
splice donor/acceptor (+/-2bp)	3	1				4
splice region				1		1
non coding			1	5	34	40
Total	5	5	33	14	50

Variants in GRHL3

This is a list of pathogenic ClinVar variants found in the GRHL3 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-24319581-C-G		Van der Woude syndrome 2	Likely benign (Apr 13, 2023)
1-24319888-G-A			Benign (Jun 20, 2021)
1-24319897-C-A			Benign (Nov 12, 2018)
1-24322926-C-T			Benign (May 12, 2021)
1-24323305-C-T			Benign (May 12, 2021)
1-24331370-A-G			Benign (May 12, 2021)
1-24331430-A-G		Isolated cleft palate	Likely pathogenic (Mar 01, 2021)
1-24331440-G-A		Isolated cleft palate • Inborn genetic diseases • GRHL3-related disorder	Conflicting classifications of pathogenicity (Jun 11, 2021)
1-24331508-A-G		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
1-24331524-C-T		GRHL3-related disorder • Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
1-24331525-G-A		Van der Woude syndrome 2	Likely benign (Apr 24, 2023)
1-24331538-A-ACAAAGGCCATGATGAGAGT			Likely pathogenic (Nov 01, 2022)
1-24331548-T-C		not specified • Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
1-24331573-C-G		not specified • Van der Woude syndrome 2	Benign (Jan 29, 2024)
1-24331582-G-A			Benign (Dec 13, 2018)
1-24331614-T-C		Van der Woude syndrome 2	Likely pathogenic (Jun 14, 2022)
1-24331621-AC-A		Van der Woude syndrome 2	Benign (Sep 13, 2022)
1-24331625-C-G		Van der Woude syndrome 2	Benign (Jun 09, 2022)
1-24334426-C-T			Benign (Nov 12, 2018)
1-24334642-C-A		Van der Woude syndrome 2	Conflicting classifications of pathogenicity (Jan 21, 2024)
1-24334661-G-A		Van der Woude syndrome 2	Benign (Apr 24, 2023)
1-24334679-C-T		Inborn genetic diseases	Uncertain significance (Jan 16, 2024)
1-24334692-T-C		GRHL3-related disorder	Likely benign (Mar 21, 2023)
1-24336215-G-GT			Benign (Jun 21, 2021)
1-24336413-G-C			Benign (May 12, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRHL3	protein_coding	protein_coding	ENST00000350501	16	45161

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.993	0.00708	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.42	284	360	0.789	0.0000208	4103
Missense in Polyphen		85	130.79	0.64988		1433
Synonymous	0.372	143	149	0.961	0.00000888	1208
Loss of Function	4.38	3	28.0	0.107	0.00000119	359

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000441	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.0000655	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin (By similarity). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (PubMed:21081122, PubMed:25347468). xhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair (By similarity). Exhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair but is essential to form the epidermal barrier with TGM3 as critical direct target gene among others. Despite being dispensable during normal epidermal homeostasis in the adulthood, is again required for barrier repair after immune-mediated epidermal damage, regulates distinct gene batteries in embryonic epidermal differentiation and adult epidermal barrier reformation after injury. Plays unique and cooperative roles with GRHL2 in establishing distinct zones of primary neurulation. Essential for spinal closure, functions cooperatively with GRHL2 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Also required for proper development of the oral periderm (PubMed:24360809). No genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity (PubMed:21081122). {ECO:0000250|UniProtKB:Q5FWH3, ECO:0000269|PubMed:12549979, ECO:0000269|PubMed:21081122, ECO:0000269|PubMed:24360809, ECO:0000269|PubMed:25347468}.

Recessive Scores

• pRec: 0.230

Intolerance Scores

• loftool: 0.450
• rvis_EVS: 0.54
• rvis_percentile_EVS: 81.09

Haploinsufficiency Scores

• pHI: 0.169
• hipred: Y
• hipred_score: 0.654
• ghis: 0.449

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.576

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Grhl3
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial 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; neoplasm; 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; 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: grhl3
• Affected structure: midbrain hindbrain boundary neural tube
• Phenotype tag: exacerbated
• Phenotype quality: morphology

Gene ontology

• Biological process: establishment of planar polarity;neural tube closure;regulation of transcription by RNA polymerase II;pattern specification process;ectoderm development;central nervous system development;epidermis development;regulation of actin cytoskeleton organization;wound healing;positive regulation of GTPase activity;positive regulation of transcription by RNA polymerase II;eyelid development in camera-type eye;establishment of skin barrier;cochlea morphogenesis;planar cell polarity pathway involved in neural tube closure
• Cellular component: nucleus;nucleoplasm
• Molecular function: 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;chromatin DNA binding;sequence-specific DNA binding