TMEM237

protein-coding

transmembrane protein 237

Gene summary

The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Previous symbols:

ALS2CR4

MANE transcript

NM_001044385.3

Inheritance

ClinVar variants

P:52U:187B:65

Top phenotype

Joubert syndrome 14

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr2:201,620,184-201,643,570

External References & Databases

Ensembl (ENSG00000155755)

Transcript & Mutation Effects

hg38 • Region Span ~23.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: G2P

Joubert syndrome 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: Natera

Joubert syndrome 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: Ambry Genetics

Joubert syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: PanelApp Australia

Joubert syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome with oculorenal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

Joubert syndrome with renal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012308

Submitter: Orphanet

Joubert syndrome 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013745

Submitter: ClinGen

The TMEM237 gene is located on chromosome 2 at 2q33.1 and encodes the transmembrane protein 237 protein. TMEM237 is a component of the transition zone in primary cilia and is required for ciliogenesis. TMEM237 was first reported in relation to autosomal recessive Joubert Syndrome 14 in 2011 (Huang et al., PMID 22152675). More than 10 unique variants (nonsense, frameshift, splice, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least nine probands in nine publications (Boycott et al., 2011 PMID 22152675; Al-Gazali et al., 2014 PMID 27081510; Lingappa et al., 2020 PMID 32139166; Alkuraya et al., 2012 PMID 22693042; Doherty et al., 2015 PMID 26092869; Alkuraya et al., 2016 PMID 27894351; Gunay-Aygun et al., 2017 PMID 28497568; Alkuraya et al., 2017 PMID 28600779; Hildebrandt et al., PMID 26673778). The mechanism of disease is loss of function (PMID 22152675). This gene-disease relationship is supported by expression studies, which show that TMEM237 is expressed in the ciliary transition zone, and a zebrafish model, which shows similar defects in eye and head development (Huang et al., 2011 PMID: 22152675). In summary, TMEM237 is definitively associated with autosomal recessive Joubert Syndrome 14. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Clinical Genomic Database (CGD)

Joubert syndrome 14AR

Manifestation: Craniofacial; 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: 17603801; 20301500; 22152675

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM237 variants in ClinVar

10 Conditions Cataloged

Joubert syndrome 14Total: 355

not providedTotal: 95

not specifiedTotal: 66

Inborn genetic diseasesTotal: 56

TMEM237-related disorderTotal: 29

Joubert syndrome and related disordersTotal: 5

Joubert syndromeTotal: 2

Meckel-Gruber syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001044385.3. 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			5 clinvar	53 clinvar	3 clinvar	61
missense		1 clinvar	176 clinvar	9 clinvar		186
nonsense	7 clinvar	8 clinvar	1 clinvar			16
start loss		1 clinvar				1
frameshift	8 clinvar	12 clinvar	2 clinvar			22
splice donor/acceptor (+/-2bp)	5 clinvar	10 clinvar	3 clinvar			18
Total	20	32	187	62	3	304

Highest pathogenic variant AF is 0.000095668045

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001044385.3	RefSeq	NP_001037850.1	13	MANE Select
ENST00000409883.7	Ensembl	ENSP00000386264.2	13	MANE Select
NM_152388.4	RefSeq	NP_689601.2	13	Standard
ENST00000286196.9	Ensembl	ENSP00000286196.5	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of Wnt signaling pathway
cilium assembly

Molecular Function

protein binding

Cellular Component

membrane
integral component of membrane
ciliary transition zone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409883
Coding exons: 13
Length: 23387
Individuals with no LoFs: 124587
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 124638
p: 0.000205

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0945	189	193	0.981	0.00000959	2582
Missense (PolyPhen)		68	66.919	1.0162		905
Synonymous	2.55	41	67.7	0.606	0.00000316	803
Loss of Function	0.639	20	23.3	0.857	0.00000132	283

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00033	0.00032	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00018	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00032	0.00031	rare
South Asian	0.00011	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the transition zone in primary cilia. Required for ciliogenesis. {ECO:0000269|PubMed:22152675}.;
Disease: DISEASE: Joubert syndrome 14 (JBTS14) [MIM:614424]: An autosomal recessive disorder characterized by severe mental retardation, hypotonia, breathing abnormalities in infancy, and dysmorphic facial features. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include renal disease, abnormal eye movements, and postaxial polydactyly. {ECO:0000269|PubMed:22152675}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.35
RVIS percentile EVS: 74.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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