TGIF1

TGFB induced factor homeobox 1, the group of TALE class homeoboxes and pseudogenes

Basic information

Region (hg38): 18:3411607-3459978

Previous symbols: [ "HPE4", "TGIF" ]

Links

ENSG00000177426 ∙ NCBI:7050 ∙ OMIM:602630 ∙ HGNC:11776 ∙ Uniprot:Q15583 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• holoprosencephaly 5 (Definitive), mode of inheritance: AD
• holoprosencephaly 4 (Strong), mode of inheritance: AD
• holoprosencephaly 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holoprosencephaly 4	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; Endocrine; Neurologic	10835638; 16199538; 20104608; 22125506; 21940735
Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TGIF1 gene.

• Holoprosencephaly 4 (61 variants)
• not provided (53 variants)
• not specified (17 variants)
• Holoprosencephaly sequence (12 variants)
• Inborn genetic diseases (5 variants)
• Disorder of sexual differentiation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TGIF1 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				16	4	20
missense	1	1	36	4	2	44
nonsense						0
start loss						0
frameshift	2	2				4
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			5	16	19	40
Total	3	3	42	36	25

Variants in TGIF1

This is a list of pathogenic ClinVar variants found in the TGIF1 region.

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

Position	Type	Phenotype	Significance	ClinVar
18-3447339-TA-T			Benign (Aug 20, 2019)
18-3447339-T-TA			Benign (Dec 13, 2019)
18-3447727-C-T			Benign (Jun 19, 2018)
18-3447827-C-G			Likely benign (Jan 09, 2019)
18-3447873-T-C			Benign (Jun 14, 2018)
18-3447963-A-G			Benign (Jun 14, 2018)
18-3448073-C-CG			Benign (Oct 30, 2019)
18-3448075-G-C			Benign (Sep 11, 2018)
18-3449607-T-TGCGCC		TGIF1-related disorder	Likely benign (Oct 15, 2020)
18-3449777-G-A		Holoprosencephaly 4	Benign (Jan 13, 2018)
18-3449779-G-C		Holoprosencephaly 4	Benign (Jan 13, 2018)
18-3449794-G-T		Holoprosencephaly 4	Benign (Jan 13, 2018)
18-3449879-A-G			Likely benign (Jun 26, 2018)
18-3450206-A-T			Benign (Oct 30, 2018)
18-3450452-A-G		not specified	Likely benign (Aug 01, 2016)
18-3450457-C-A		not specified • Holoprosencephaly sequence	Benign (Jun 14, 2016)
18-3450514-G-A		Holoprosencephaly 4	Likely benign (Oct 07, 2022)
18-3450515-C-T		Holoprosencephaly 4 • TGIF1-related disorder	Likely benign (Oct 13, 2023)
18-3450516-C-G		Holoprosencephaly 4	Likely benign (Apr 17, 2021)
18-3450519-G-A		Holoprosencephaly 4	Likely benign (Apr 10, 2021)
18-3451390-C-CAA			Benign (Oct 30, 2019)
18-3451541-GA-G			Benign (Jun 14, 2018)
18-3451632-G-C		TGIF1-related disorder	Likely benign (Apr 07, 2023)
18-3451764-C-T			Benign (Jun 14, 2018)
18-3451773-T-G			Uncertain significance (Mar 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TGIF1	protein_coding	protein_coding	ENST00000330513	3	46804

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0105	0.950	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.178	225	233	0.967	0.0000128	2550
Missense in Polyphen		30	66.247	0.45285		793
Synonymous	-0.651	107	98.8	1.08	0.00000540	904
Loss of Function	1.78	5	11.5	0.433	5.14e-7	127

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII- RXRE). Inhibits the 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element. Active transcriptional corepressor of SMAD2. Links the nodal signaling pathway to the bifurcation of the forebrain and the establishment of ventral midline structures. May participate in the transmission of nuclear signals during development and in the adult, as illustrated by the down-modulation of the RXR alpha activities.
• Disease: DISEASE: Holoprosencephaly 4 (HPE4) [MIM:142946]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. {ECO:0000269|PubMed:10835638, ECO:0000269|PubMed:15221788}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);TGF-Ncore;Androgen receptor signaling pathway;TGF-beta Signaling Pathway;Tgif disruption of Shh signaling;TGF-beta Receptor Signaling;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Downregulation of SMAD2/3:SMAD4 transcriptional activity;AndrogenReceptor;TGF_beta_Receptor;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;EGFR1;Coregulation of Androgen receptor activity;Signaling by TGF-beta Receptor Complex;Signaling by TGF-beta family members;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.101

Intolerance Scores

• loftool: 0.310
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.41

Haploinsufficiency Scores

• pHI: 0.107
• hipred: Y
• hipred_score: 0.597
• ghis: 0.562

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.990

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tgif1
• Phenotype: skeleton phenotype; immune system phenotype; vision/eye phenotype; hearing/vestibular/ear 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; 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; reproductive system 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; taste/olfaction phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: tgif1
• Affected structure: Muller cell
• Phenotype tag: abnormal
• Phenotype quality: molecular quality

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;multicellular organism development;response to drug;cellular response to growth factor stimulus
• Cellular component: nucleoplasm
• 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;transcription corepressor activity;protein binding;co-SMAD binding