• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TFAP2B (HGNC:11743) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
transcription factor AP-2 beta
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
AP2-B, AP-2beta
%HI
2.98(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.99(Read more about gnomAD pLI score)
LOEUF
0.26(Read more about gnomAD LOEUF score)
Cytoband
6p12.3
Genomic Coordinates
GRCh37/hg19: chr6:50786584-50815332 NCBI Ensembl UCSC
GRCh38/hg38: chr6:50818355-50847619 NCBI Ensembl UCSC
MANE Select Transcript
NM_003221.4 ENST00000393655.4 (Read more about MANE Select)
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-beta appears to be required for normal face and li... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-24186
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Assoc. with Reduced Penetrance:
Yes
Last Evaluated:
04/11/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 21643846
    Chen et al. (2011) describe two variants affecting splicing (c.601+5G>A [same variant as previously observed in Mani et al., but unrelated kindred] and c.435_438delCCGG in kindreds with apparently isolated familial patent ductus arteriosus (PDA). Neither variant was found in the unaffected members of the kindred or in a group of 100 ethnically-matched controls. The authors predicted that these variants would result in loss of function. Subsequent functional studies described in Ji et al (2014, PMID 24507797) report that the c.435_438delCCGG mutation produced a truncated protein (which also did not inhibit function of the wild type protein), whereas the c.601+5G>A mutation did not produce any detectable protein. The authors concluded that haploinsufficiency was the mechanism by which these variants caused the phenotypes in their respective kindreds.
  • PUBMED: 24507797
    Ji et al (2014) performed functional studies on the two variants previously described by Chen et al (2011, PMID: 21643846) and report that the c.435_438delCCGG mutation produced a truncated protein (which also did not inhibit function of the wild type protein), whereas the c.601+5G>A mutation did not produce any detectable protein. The authors concluded that haploinsufficiency was the mechanism by which these variants caused the phenotypes in their respective kindreds.
  • PUBMED: 15684060
    Mani et al. (2005) described two kindreds with Char syndrome. Kindred K144 resulted in a splice site missense mutation in 22 affected members with variable features of Char, and was compatible with autosomal dominant transmission. Patent ductus arteriosis showed incomplete penetrance whereas the dysmorphic facies and clinodactyly showed evidence of high penetrance. One obligate carrier of this kindred was non-penetrant. Kindred K145 resulted in a splice site missense mutation. 4 of 5 affected individuals described had patent ductus arteriosis, dysmorphic facies and clinodactyly (one was not described in the paper). Both these mutations were absent in 200 unrelated control chromosomes. Mutation K144 were found to alter normal splicing using a biochemical splicing assay. This assay demonstrated abnormal splicing - either complete exon skipping or a mixture of exon splice products, thereby susceptible to nonsense mediated decay. No assay was performed for the K145 mutation; however authors highlighted that there is no doubt that this would disrupt normal splicing.
  • PUBMED: 30579973
    Massaad et al (2019) report a case study of a 13 month old male proband with a de novo frameshift variant (c.650delG) detected by trio exome sequencing. Upon examination, he had mainly musculoskeletal and facial features of Char syndrome. A PFO was identified at 2 years of age by echocardiogram, but no PDA was identified. Motor and cognitive milestones were concordant for chronological age. Per the authors, since the echo was not performed until 2 years of age, there is no way to confirm whether this proband originally had a PDA that spontaneously closed. This paper also suggests PDA identification maybe overlooked or missed during clinical assessment because of its transient nature.
  • PUBMED: 31292255
    Timberlake et al (2019) described a cohort of 12 patients with syndromic craniosynostosis, where prior genetic testing was done and noncontributory to disease diagnosis. 4 of 12 probands were found to have sequence variants in TFAP2B: 2 denovo (1 LOF, 1 missense) and 2 inherited (both were LOF variants). Prior studies referenced in this paper have also noted abnormal head shape and ridging, but this previously was not discussed as part of the overarching syndrome phenotype of Char syndrome. 1 proband from this cohort was diagnosed with a spontaneously closing PDA by age 7. All 3 probands with LOF variants also had variable clinical features of Char syndrome, as well as susceptibility to infections. This paper contributes to the literature in suggesting that there is a broader range of phenotypes resulting from haploinsufficiency of TFAP2B than previously recognized, highlighting pleiotropy and variable expressivity.
HI Evidence Comments:
Variants in TFAP2B, resulting in both dominant negative effects and functional haploinsufficiency, have been associated with Char syndrome. Char syndrome is characterized by patent ductus arteriosus, dysmorphic facial features, and finger anomalies, and exhibits variable expressivity and reduced penetrance. Craniosynostosis has also been noted as an emerging feature. Parasomnia, dental and occipital bone abnormalities have also been described. Isolated PDA has also been seen in kindreds with functional haploinsufficiency of TFAP2B. For additional information regarding dominant negative variants and Char syndrome, see PMIDs 10802654, 10368122, and 11505339.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000006.11) (NC_000006.12)