TFE3

protein-coding

transcription factor binding to IGHM enhancer 3, the group of Basic helix-loop-helix proteins

Gene summary

This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling. This gene may be involved in chromosomal translocations in renal cell carcinomas and other cancers, resulting in the production of fusion proteins. Translocation partners include PRCC (papillary renal cell carcinoma), NONO (non-POU domain containing, octamer-binding), and ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), among other genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

MANE transcript

NM_006521.6

Inheritance

XL, AD

ClinVar variants

P:19U:108B:24

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:49,028,726-49,043,410

External References & Databases

Ensembl (ENSG00000068323)

Transcript & Mutation Effects

hg38 • Region Span ~14.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:1040018

Submitter: ClinGen

*TFE3* variants were first reported in connection with X-linked syndromic complex neurodevelopmental disorder in 2019 by a program designed to identify genetic casualties of Hypomelanosis of Ito (Villegas et al., 2019; PMID: 30595499). Affected individuals are characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism. Additional clinical features may include epilepsy, orthopedic abnormalities, hypotonia, and growth abnormalities. Thirteen *de novo* variants (12 missense, 1 canonical splice site) reported in four publications were included in this curation (PMIDs: 30595499, 31833172, 32409512, 35503477). One variant has been reported at a mosaic state in at least two male patients. Thus far, *TFE3* variants causative of the disorder are located in exons 3 and 4. Functional evidence indicates that the absence of either *TFE3* exon 3 or 4 results in a nuclear gain-of-function Tfe3 allele in Embryonic Stem Cells (ESCs), indicating that both exons are required for Tfe3 inactivation (PMID: 30595499). The maximum score for genetic evidence (12 pts.) has been reached. No convincing experimental evidence supports this gene-disease relationship. Tfe3 KO mice demonstrate significant abnormalities in energy balance and alterations in systemic glucose and lipid metabolism, resulting in enhanced diet‐induced obesity and diabetes (PMID: 28283651). Metabolic anomalies are observed in patients affected by this disorder, suggesting that the gene may be important for metabolic signaling and lipid metabolism in both mice and humans. However, due to lack of construct validity (the difference in mechanism of pathogenicity between mice and humans), this mouse model was not scored. In summary, there is Definitive evidence to support the relationship between *TFE3* and X-linked syndromic complex neurodevelopmental disorder. 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 Intellectual Disability and Autism expert panel on March 19th, 2024 (SOP Version 10).

intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse faciesDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0859080

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse faciesSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0859080

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse faciesSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0859080

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse faciesXL

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; 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

Refs: 30595499; 31833172

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFE3 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 68

Inborn genetic diseasesTotal: 48

Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse faciesTotal: 25

TFE3-related disorderTotal: 6

not specifiedTotal: 4

Renal cell carcinoma, Xp11-associatedTotal: 3

Neurodevelopmental disorderTotal: 1

Renal cell carcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006521.6. 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			5 clinvar	7 clinvar		12
missense	8 clinvar	10 clinvar	92 clinvar	16 clinvar	1 clinvar	127
nonsense						0
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar		8 clinvar			9
Total	9	10	108	23	1	151

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006521.6	RefSeq	NP_006512.2	10	MANE Select
ENST00000315869.8	Ensembl	ENSP00000314129.7	10	MANE Select
NM_001282142.2	RefSeq	NP_001269071.1	8	Standard
ENST00000493583.5	Ensembl	ENSP00000476976.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renal cell carcinoma - Homo sapiens (human)
Mitophagy - animal - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)
Type 2 papillary renal cell carcinoma
TGF-beta Receptor Signaling

Biological Process

adaptive immune response
humoral immune response
regulation of osteoclast differentiation
positive regulation of cell adhesion
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
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

Cellular Component

nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315869
Coding exons: 10
Length: 14771
Individuals with no LoFs: 125660
Homozygous LoFs: 2
Heterozygous LoFs: 1
Defined: 125663
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.15	140	232	0.602	0.0000197	3639
Missense (PolyPhen)		14	19.607	0.71401		262
Synonymous	0.830	92	103	0.896	0.00000879	1266
Loss of Function	3.52	1	16.3	0.0612	0.00000131	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000093	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000076	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that specifically recognizes and binds E-box sequences (5'-CANNTG-3'). Efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFEB or MITF. In association with TFEB, activates the expression of CD40L in T-cells, thereby playing a role in T- cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity. Specifically recognizes the MUE3 box, a subset of E-boxes, present in the immunoglobulin enhancer. It also binds very well to a USF/MLTF site.;
Disease: DISEASE: Note=A chromosomal aberration involving TFE3 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with ASPSCR1 forms a ASPSCR1-TFE3 fusion protein. {ECO:0000269|PubMed:11358836}.; DISEASE: Note=Chromosomal aberrations involving TFE3 are found in patients with papillary renal cell carcinoma. Translocation t(X;1)(p11.2;q21.2) with PRCC; translocation t(X;1)(p11.2;p34) with PSF; inversion inv(X)(p11.2;q12) that fuses NONO to TFE3. {ECO:0000269|PubMed:8872474, ECO:0000269|PubMed:8986805}.;

Recessive Scores

pRec: 0.242

Intolerance Scores

LoFtool: 0.192
RVIS EVS: 0.51
RVIS percentile EVS: 80.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.170

Gene Damage Prediction

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