GeneBe

GRHL3

protein-coding

grainyhead like transcription factor 3

Gene summary

This gene encodes a member of the grainyhead family of transcription factors. The encoded protein may function as a transcription factor during development, and has been shown to stimulate migration of endothelial cells. Multiple transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Aug 2010]

Previous symbols:
  • TFCP2L4

MANE transcript

NM_198173.3

Inheritance

AD

ClinVar variants

P:26U:118B:54

Top phenotype

van der Woude syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr1:24,199,558-24,364,482

External References & Databases

Ensembl (ENSG00000158055)NCBI Gene (57822)OMIM (608317)HGNC:25839GenCCUniProt (Q8TE85)AlphaFoldClinVar (GRHL3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~164.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

van der Woude syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011712

Submitter: PanelApp Australia

van der Woude syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019508

Submitter: Orphanet

van der Woude syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011712

Submitter: G2P

van der Woude syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011712

Submitter: Ambry Genetics

GRHL3-related orofacial cleftingDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100579

Submitter: ClinGen

*GRHL3* was first reported in relation to autosomal dominant GRHL3-related orofacial clefting in 2014 (Peyrard-Janvid et al., PMID: 24360809). GRHL3-related orofacial clefting is characterized by lower lip pits; cleft lip; cleft palate; and uvular anomaly. 9 variants (missense, nonsense, frameshift, splicing) that have been reported in at least 9 probands in 5 publications (PMIDs: 24360809, 27018475, 28886269, 34459660, 36901693) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, zebrafish model; PMID: 24360809). The mouse and zebrafish models demonstrate that mutants have disrupted periderm development, atypical oral periderm, lack of epistasis, and, occasionally, cleft palate. In summary, there is definitive evidence supporting the relationship between *GRHL3* and autosomal dominant GRHL3-related orofacial clefting. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 1/18/2024 (SOP Version 10).

van der Woude syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011712

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

van der Woude syndrome 2AD

Manifestation: Craniofacial; Dental; Musculoskeletal

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: 24360809Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRHL3 variants in ClinVar

9 Conditions Cataloged
Inborn genetic diseasesTotal: 88
Van der Woude syndrome 2Total: 74
GRHL3-related disorderTotal: 50
not providedTotal: 42
not specifiedTotal: 18
Isolated cleft palateTotal: 8
GRHL3-related disordersTotal: 2
Van der Woude syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198173.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
26
clinvar
4
clinvar
 33
missense
1
clinvar
4
clinvar
112
clinvar
18
clinvar
6
clinvar
 141
nonsense
2
clinvar
2
clinvar
 4
start loss
0
frameshift
3
clinvar
6
clinvar
1
clinvar
 10
splice donor/acceptor (+/-2bp)
5
clinvar
2
clinvar
3
clinvar
 10
Total11151184410198

Highest pathogenic variant AF is 0.000018598077

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_198173.3RefSeqNP_937816.116MANE Select
ENST00000361548.9EnsemblENSP00000354943.516MANE Select
NM_001195010.2RefSeqNP_001181939.115Standard
NM_021180.4RefSeqNP_067003.216Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
grhl3Danio rerio

Structure: midbrain hindbrain boundary neural tube

Quality: morphology

exacerbated

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • establishment of planar polarity
  • neural tube closure
  • regulation of transcription by RNA polymerase II
  • pattern specification process
  • ectoderm development

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

Cellular Component

  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000350501
Coding exons
16
Length
45161
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125748
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.422843600.7890.00002084103
Missense (PolyPhen)85130.790.649881433
Synonymous0.3721431490.9610.000008881208
Loss of Function4.38328.00.1070.00000119359

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian0.0000660.000065rare
Other00.0absent

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.576

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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