TMEM127

protein-coding

transmembrane protein 127

Gene summary

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]

MANE transcript

NM_017849.4

Inheritance

ClinVar variants

P:137U:638B:271

Top phenotype

Pheochromocytoma

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr2:96,248,500-96,266,047

External References & Databases

Ensembl (ENSG00000135956)

Transcript & Mutation Effects

hg38 • Region Span ~17.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: Ambry Genetics

pheochromocytomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: PanelApp Australia

pheochromocytomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: Labcorp Genetics (formerly Invitae)

hereditary pheochromocytoma-paragangliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: ClinGen

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to Paraganglioma such as head and neck, retroperitoneum [PMID: 21613359], or Renal cell carcinomas (RCCs) [PMID 24334765] and Pheochromocytoma [MIM#171300, PMID: 21156949] with autosomal dominant inheritance. TMEM127 [MIM# 613403] gene encodes the transmembrane protein 127. Heterozygous germline loss of function variants in TMEM127 were first described in 2005 [Dahia PL, et al.; PMID 16266984]. The LOH (loss of heterozygosity) at the TMEM127 locus in tumors examined suggests TMEM127 is a tumor suppressor gene. Genetic evidence from studies on familial and patients with sporadic Pheochromocytomas, as well as RCC are used in this curation [PMID 16266984, 25389632, 20154675 and 28384794]. Experimental evidences such as reduced TMEM127 transcription levels of TMEM127-mutant tumor samples in Pheochromocytomas and Renal cell carcinomas; reduced mTOR signaling, enlarged cells, reduced vesicles and/or increased cell growth compared to non mutant controls in various human cells and murine model cells with reduced or depleted TMEM127 are included for this curation. Evidence that the enlarged cells and increased cell proliferation were rescued by enforced expression of TMEM127 is also included [PMID 20154675, 21156949, 24334765]. In summary, TMEM127 gene is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

pheochromocytomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008233

Submitter: G2P

renal cell carcinomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005086

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

PheochromocytomaAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Surveillance and awareness of cancer risk may allow early diagnosis and treatment of neoplasms, which may reduce morbidity and mortality

Comments: Although adults have been reported, surveillance in the pediatric period may nevertheless be warranted

Refs: 20154675; 22419703; 23666964

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM127 variants in ClinVar

16 Conditions Cataloged

Hereditary cancer-predisposing syndromeTotal: 817

Hereditary pheochromocytoma and paragangliomaTotal: 757

not providedTotal: 153

PheochromocytomaTotal: 123

not specifiedTotal: 41

TMEM127-related disorderTotal: 34

PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 8Total: 7

Inherited phaeochromocytoma and paraganglioma excluding NF1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017849.4. 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			4 clinvar	259 clinvar		263
missense		8 clinvar	617 clinvar	11 clinvar	1 clinvar	637
nonsense	16 clinvar	13 clinvar	6 clinvar			35
start loss	7 clinvar	2 clinvar	2 clinvar			11
frameshift	57 clinvar	20 clinvar	6 clinvar			83
splice donor/acceptor (+/-2bp)	5 clinvar	9 clinvar	3 clinvar			17
Total	85	52	638	270	1	1046

Highest pathogenic variant AF is 0.000016379108

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017849.4	RefSeq	NP_060319.1	3	MANE Select
ENST00000258439.8	Ensembl	ENSP00000258439.3	3	MANE Select
NM_001193304.3	RefSeq	NP_001180233.1	3	Standard
NM_001407282.1	RefSeq	NP_001394211.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

endosome organization
negative regulation of cell population proliferation
negative regulation of TOR signaling

Molecular Function

molecular_function
Rab GTPase binding

Cellular Component

cytoplasm
early endosome
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258439
Coding exons: 3
Length: 17479
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.448	123	138	0.893	0.00000808	1489
Missense (PolyPhen)		35	43.27	0.80887		495
Synonymous	-0.112	66	64.9	1.02	0.00000398	531
Loss of Function	1.29	4	7.92	0.505	3.41e-7	96

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1. May act as a tumor suppressor. {ECO:0000269|PubMed:20154675}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.116
RVIS EVS: -0.05
RVIS percentile EVS: 49.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.666

Gene Damage Prediction

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