TMEFF2

Chr 2

transmembrane protein with EGF like and two follistatin like domains 2

Also known as: CT120.2, HPP1, TENB2, TPEF, TR, TR-2

NCBI Gene: 23671 ENSG00000144339 UniProt: Q9UIK5 OMIM: 605734

This gene encodes a transmembrane protein from the tomoregulin family that functions as a survival factor for hippocampal and mesencephalic neurons and can regulate cell proliferation through ERK1/2 signaling. The gene is not well-established in pediatric neurogenetic disorders, with constraint metrics (pLI 0.00007, LOEUF 0.739) indicating tolerance to loss-of-function variants. Current evidence primarily links this gene to cancer biology rather than inherited neurological conditions.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the tomoregulin family of transmembrane proteins. This protein has been shown to function as both an oncogene and a tumor suppressor depending on the cellular context and may regulate prostate cancer cell invasion. Multiple soluble forms of this protein have been identified that arise from both an alternative splice variant and ectodomain shedding. Additionally, this gene has been found to be hypermethylated in multiple cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.74

Clinical Summary— TMEFF2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 2.54

OE 0.45 (0.28–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.60Z-score

OE missense 0.69 (0.60–0.79)

140 obs / 204.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.28–0.74)

0≤0.351.4

Missense OE?0.69 (0.60–0.79)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 11 / 24.6Missense obs/exp: 140 / 204.4Syn Z: 0.79

This gene — mechanism propensity

0.7131th %ile

GOF

0.7126th %ile

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.