TFE3

Chr XX-linked

transcription factor binding to IGHM enhancer 3

Also known as: MRXSPF, RCCP2, RCCX1, TFEA, bHLHe33

NCBI Gene: 7030 ENSG00000068323 UniProt: P19532 OMIM: 314310

TFE3 encodes a transcription factor that regulates lysosomal biogenesis and cellular responses to nutrient availability by binding to specific DNA sequences and promoting expression of lysosomal genes. Mutations cause X-linked intellectual developmental disorder with syndromic features including pigmentary mosaicism and coarse facies. The gene follows X-linked inheritance and is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.29).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, with pigmentary mosaicism and coarse faciesMIM #301066

X-linked

Renal cell carcinoma, papillary, 1MIM #300854

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · X-linked syndromic complex neurodevelopmental disorder · XL · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

337

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.29

LOEUF· LoF intol.

LOF

Mechanism· predicted

📖

GeneReview available — TFE3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.29LOEUF

pLI 0.980

Z-score 3.52

OE 0.06 (0.02–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.15Z-score

OE missense 0.60 (0.52–0.69)

140 obs / 232.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.29)

0≤0.351.4

Missense OE?0.60 (0.52–0.69)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 16.3Missense obs/exp: 140 / 232.4Syn Z: 0.83

Background carrier burden — how many people carry a rare variant somewhere in TFE3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

400 rare PASS variants

Rare truncating (LoF)

1 in 14,000

14 rare PASS variants

Rare synonymous (reference)

1 in 270

226 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TFE3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 200	1 in 110,000
South Asian	~36k	1 in 150	≈ 1 in 33,000
Remaining (unassigned)	~31k	1 in 130	none seen
European (Finnish)	~27k	1 in 300	1 in 2,200
Admixed American	~23k	1 in 160	none seen
African / African American	~21k	1 in 230	1 in 3,800
East Asian	~20k	1 in 200	≈ 1 in 9,500
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 190	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓