TFAP2A

protein-coding

transcription factor AP-2 alpha, the group of Transcription factor AP-2 family

Gene summary

The protein encoded by this gene is a transcription factor that binds the consensus sequence 5'-GCCNNNGGC-3'. The encoded protein functions as either a homodimer or as a heterodimer with similar family members. This protein activates the transcription of some genes while inhibiting the transcription of others. Defects in this gene are a cause of branchiooculofacial syndrome (BOFS). Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2009]

Previous symbols:

TFAP2
AP2TF

MANE transcript

NM_001372066.1

Inheritance

ClinVar variants

P:55U:130B:62

Top phenotype

Branchiooculofacial sydrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr6:10,393,186-10,419,659

External References & Databases

Ensembl (ENSG00000137203)

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

branchiooculofacial syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007235

Submitter: PanelApp Australia

branchiooculofacial syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007235

Submitter: Labcorp Genetics (formerly Invitae)

branchiooculofacial syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007235

Submitter: Orphanet

branchiooculofacial syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007235

Submitter: G2P

Clinical Genomic Database (CGD)

Branchiooculofacial sydromeAD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: The condition may be recognizable due to the presence of a specific pattern of congenital malformations affecting hearing as well as multiple organ systems; An individual with medulloblastoma has been described

Refs: 1619642; 7747785; 9761567; 18423521; 19685247; 19764023; 19206157; 20358615; 20635357; 21634087; 21204207

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFAP2A variants in ClinVar

21 Conditions Cataloged

not providedTotal: 207

Branchiooculofacial syndromeTotal: 83

Inborn genetic diseasesTotal: 37

TFAP2A-related disorderTotal: 18

not specifiedTotal: 4

EsotropiaTotal: 1

EEG abnormalityTotal: 1

Short neckTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001372066.1. 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			3 clinvar	54 clinvar	3 clinvar	60
missense	14 clinvar	22 clinvar	121 clinvar	4 clinvar	1 clinvar	162
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss						0
frameshift	3 clinvar	5 clinvar	2 clinvar			10
splice donor/acceptor (+/-2bp)		4 clinvar	3 clinvar			7
Total	20	35	130	58	4	247

Highest pathogenic variant AF is 0.0000065741897

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001372066.1	RefSeq	NP_001358995.1	7	MANE Select
ENST00000379613.10	Ensembl	ENSP00000368933.5	7	MANE Select
NM_001032280.3	RefSeq	NP_001027451.1	7	Standard
NM_001042425.3	RefSeq	NP_001035890.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tfap2a	Danio rerio	Structure: hematopoietic multipotent progenitor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tfap2a

Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neural Crest Differentiation
Corticotropin-releasing hormone signaling pathway
Ectoderm Differentiation
Hypothetical Craniofacial Development Pathway
Ebola Virus Pathway on Host

Biological Process

negative regulation of transcription by RNA polymerase II
kidney development
optic vesicle morphogenesis
optic cup structural organization
regulation of transcription by RNA polymerase II

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
proximal promoter sequence-specific DNA binding

Cellular Component

nucleus
nucleoplasm
Golgi apparatus
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379604
Coding exons: 7
Length: 26474
Individuals with no LoFs: 124526
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124528
p: 0.00000803

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.59	136	251	0.541	0.0000123	2822
Missense (PolyPhen)		48	120.71	0.39763		1426
Synonymous	-1.36	129	111	1.16	0.00000592	894
Loss of Function	3.73	1	18.2	0.0551	8.33e-7	204

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. AP-2-alpha is the only AP-2 protein required for early morphogenesis of the lens vesicle. Together with the CITED2 coactivator, stimulates the PITX2 P1 promoter transcription activation. Associates with chromatin to the PITX2 P1 promoter region. {ECO:0000269|PubMed:11694877, ECO:0000269|PubMed:12586840}.;
Disease: DISEASE: Branchiooculofacial syndrome (BOFS) [MIM:113620]: A syndrome characterized by growth retardation, bilateral branchial sinus defects with hemangiomatous, scarred skin, cleft lip with or without cleft palate, pseudocleft of the upper lip, nasolacrimal duct obstruction, low set ears with posterior rotation, a malformed, asymmetrical nose with a broad bridge and flattened tip, conductive or sensorineural deafness, ocular and renal anomalies. {ECO:0000269|PubMed:18423521}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.954

Intolerance Scores

LoFtool: 0.0164
RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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