TGIF1

protein-coding

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

Gene summary

The protein encoded by this gene is a member of the three-amino acid loop extension (TALE) superclass of atypical homeodomains. TALE homeobox proteins are highly conserved transcription regulators. This particular homeodomain binds to a previously characterized retinoid X receptor responsive element from the cellular retinol-binding protein II promoter. In addition to its role in inhibiting 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element, the protein is an active transcriptional co-repressor of SMAD2 and may participate in the transmission of nuclear signals during development and in the adult. Mutations in this gene are associated with holoprosencephaly type 4, which is a structural anomaly of the brain. Alternative splicing has been observed at this locus and multiple splice variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2013]

Previous symbols:

HPE4
TGIF

MANE transcript

NM_003244.4

Inheritance

ClinVar variants

P:10U:66B:32

Top phenotype

Holoprosencephaly 4

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr18:3,411,608-3,459,978

External References & Databases

Ensembl (ENSG00000177426)

Transcript & Mutation Effects

hg38 • Region Span ~48.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephaly 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007734

Submitter: PanelApp Australia

holoprosencephaly 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007734

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

holoprosencephaly 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007734

Submitter: Labcorp Genetics (formerly Invitae)

holoprosencephaly 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007734

Submitter: Ambry Genetics

holoprosencephaly 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007734

Submitter: G2P

Clinical Genomic Database (CGD)

Holoprosencephaly 4AD

Manifestation: Craniofacial; Endocrine; Neurologic

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

Comments: Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

Refs: 10835638; 16199538; 20104608; 22125506; 21940735

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TGIF1 variants in ClinVar

6 Conditions Cataloged

Holoprosencephaly 4Total: 80

not providedTotal: 51

Inborn genetic diseasesTotal: 21

TGIF1-related disorderTotal: 14

not specifiedTotal: 11

Disorder of sexual differentiationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003244.4. 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				22 clinvar	4 clinvar	26
missense	2 clinvar	2 clinvar	64 clinvar	3 clinvar	3 clinvar	74
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	3	7	66	25	7	108

Highest pathogenic variant AF is 0.00012328578

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003244.4	RefSeq	NP_003235.1	3	MANE Select
ENST00000343820.10	Ensembl	ENSP00000339631.6	3	MANE Select
NM_001278682.2	RefSeq	NP_001265611.1	3	Standard
NM_001278684.2	RefSeq	NP_001265613.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tgif1	Danio rerio	Structure: Muller cell Quality: molecular quality abnormal

Gene / Model

Organism

Observed Phenotype

tgif1

Danio rerio

Structure: Muller cell

Quality: molecular quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
TGF-Ncore
Androgen receptor signaling pathway
TGF-beta Signaling Pathway
Tgif disruption of Shh signaling

Biological Process

negative regulation of transcription by RNA polymerase II
multicellular organism development
response to drug
cellular response to growth factor stimulus

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

Cellular Component

nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330513
Coding exons: 3
Length: 46804
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.178	225	233	0.967	0.0000128	2550
Missense (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

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.310
RVIS EVS: 0.04
RVIS percentile EVS: 57.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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