TMEM127

Chr 2AD

transmembrane protein 127

NCBI Gene: 55654 ENSG00000135956 UniProt: O75204 OMIM: 613403

TMEM127 encodes a transmembrane protein that localizes to endosomes, Golgi, and lysosomes where it participates in protein trafficking and controls cell proliferation by negatively regulating mTORC1 signaling. Mutations cause autosomal dominant susceptibility to pheochromocytoma, typically presenting in adulthood. The gene shows low constraint against loss-of-function variants, which is consistent with its role as a tumor suppressor gene.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.151 OMIM phenotype

Clinical Summary— TMEM127

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Gene-Disease Validity (ClinGen)

hereditary pheochromocytoma-paraganglioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.013

Z-score 1.29

OE 0.50 (0.25–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.45Z-score

OE missense 0.89 (0.77–1.04)

123 obs / 137.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.25–1.15)

0≤0.351.4

Missense OE?0.89 (0.77–1.04)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 4 / 7.9Missense obs/exp: 123 / 137.8Syn Z: -0.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTMEM127-related pheochromocytoma, susceptibility toLOFAD

This gene — mechanism propensity

0.4785th %ile

GOF

0.6833th %ile

LOF

0.3551th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.

Literature Evidence

LOFYao et al (2010) sequenced the TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without variants in other susceptibility genes from 8 independent worldwide referral centers. They identified 10 loss of function variants including 1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References