TMEM138

protein-coding

transmembrane protein 138

Gene summary

This gene encodes a multi-pass transmembrane protein. Reduced expression of this gene in mouse fibroblasts causes short cilia and failure of ciliogenesis. Expression of this gene is tightly coordinated with expression of the neighboring gene TMEM216. Mutations in this gene are associated with the autosomal recessive neurodevelopmental disorder Joubert Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

MANE transcript

NM_016464.5

Inheritance

ClinVar variants

P:18U:72B:34

Top phenotype

Joubert syndrome 16

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr11:61,361,964-61,377,890

External References & Databases

Ensembl (ENSG00000149483)

Transcript & Mutation Effects

hg38 • Region Span ~15.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013764

Submitter: G2P

Joubert syndrome with oculorenal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

ciliopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The *TMEM138* gene is located on chromosome 11q12.2 and encodes the Transmembrane protein 138. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanisms, inheritance pattern, and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Joubert syndrome 16 (OMIM: 614465; PMIDs: 22282472, 27081510, 27434533, 26489029, 28102635, 29620724, 34821546, 34354814); Meckel syndrome (PMIDs: 22282472, 23351400, 27894351); and Orofaciodigital syndrome (PMID: 28289185, 27434533). The preferred disease name suggested for this disorder is autosomal recessive ciliopathy-*TMEM138*. *TMEM138* was first reported in relation to ciliopathy-*TMEM138* in 2012 (Lee et al., PMID: 22282472). The mechanism of pathogenicity appears to be loss-of-function. The reported patients presented clinical features consistent with ciliopathies including neurodevelopmental delay, molar tooth sign on brain MRI, encephalocele, ocular coloboma, oculomotor apraxia, cystic kidney disease, nephronophthisis, and polydactyly. 11 variants (missense, splice site, frameshift) reported in 21 probands in 13 publications (PMIDs: 22282472, 28102635, 23351400, 34821546, 27081510, 27434533, 34354814, 29620724, 26489029, 27894351, 28289185, 39891418, 40448720) are included in this curation. The majority of the variants were missense, with functional data indicating that missense variants result in decreased production of wild-type protein and shortened cilia in patient fibroblasts (PMID: 22282472). This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 22282472, 35394880, 41747882). It is shown that the gene is expressed in all major tissues and that inactivation leads to ciliopathy-like features in model systems. The protein is crucial for ciliary assembly and interacts with other ciliopathy proteins. In summary, there is Moderate evidence supporting the relationship between *TMEM138* and ciliopathy-*TMEM138*. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 04/25/2023 (SOP Version 9). This gene-disease relationship was re-evaluated on June 8th, 2026 by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP (SOP Version 12). Two new case reports and a conditional mouse model were included in the recuration (PMIDs: 39891418, 40448720, 41747882). As a result of this re-evaluation, the classification did not change.

Joubert syndrome 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013764

Submitter: PanelApp Australia

Joubert syndrome 16MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013764

Submitter: Ambry Genetics

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

Joubert syndrome 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013764

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Joubert syndrome 16AR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic; Renal

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

Comments: The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial;

Refs: 22282472; 20301500

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM138 variants in ClinVar

8 Conditions Cataloged

Joubert syndrome 16Total: 144

not providedTotal: 39

not specifiedTotal: 23

Inborn genetic diseasesTotal: 15

TMEM138-related disorderTotal: 12

Joubert syndrome and related disordersTotal: 2

Meckel-Gruber syndromeTotal: 1

Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016464.5. 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				30 clinvar	1 clinvar	31
missense		4 clinvar	66 clinvar	3 clinvar		73
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss						0
frameshift	2 clinvar	6 clinvar	4 clinvar			12
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	5	13	72	33	1	124

Highest pathogenic variant AF is 0.000022307266

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016464.5	RefSeq	NP_057548.1	4	MANE Select
ENST00000278826.11	Ensembl	ENSP00000278826.5	4	MANE Select
NM_001330281.2	RefSeq	NP_001317210.1	3	Standard
NM_001410997.1	RefSeq	NP_001397926.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cilium assembly

Cellular Component

vacuolar membrane
cilium
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278826
Coding exons: 4
Length: 7509
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125747
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.473	75	87.4	0.858	0.00000456	1069
Missense (PolyPhen)		26	32.992	0.78806		423
Synonymous	-0.165	36	34.8	1.04	0.00000174	312
Loss of Function	1.40	3	7.00	0.429	2.97e-7	79

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for ciliogenesis. {ECO:0000269|PubMed:22282472}.;
Disease: DISEASE: Joubert syndrome 16 (JBTS16) [MIM:614465]: An autosomal recessive disorder characterized by oculomotor apraxia, variable coloboma, and rare kidney involvement. Neuroradiologically, it is characterized by an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and polydactyly. {ECO:0000269|PubMed:22282472}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.302
RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.132

Gene Damage Prediction

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