TMEM67

transmembrane protein 67, the group of MKS complex

Basic information

Region (hg38): 8:93754843-93819234

Previous symbols: [ "MKS3" ]

Links

ENSG00000164953 ∙ NCBI:91147 ∙ OMIM:609884 ∙ HGNC:28396 ∙ Uniprot:Q5HYA8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• COACH syndrome 1 (Definitive), mode of inheritance: AR
• nephronophthisis 11 (Definitive), mode of inheritance: AR
• Meckel syndrome (Supportive), mode of inheritance: AR
• Joubert syndrome (Supportive), mode of inheritance: AR
• COACH syndrome 1 (Supportive), mode of inheritance: AR
• Senior-Boichis syndrome (Supportive), mode of inheritance: AR
• COACH syndrome 1 (Strong), mode of inheritance: AR
• Joubert syndrome 6 (Strong), mode of inheritance: AR
• Meckel syndrome, type 3 (Definitive), mode of inheritance: AR
• nephronophthisis 11 (Moderate), mode of inheritance: AR
• Joubert syndrome 6 (Strong), mode of inheritance: AR
• nephronophthisis 11 (Strong), mode of inheritance: AR
• ciliopathy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
COACH syndrome 1	AR	Gastrointestinal	In COACH syndrome, among other findings, individuals may have hepatic disease, and it has been suggested that identification of liver disease is critical as some patients may develop complications such as portal hypertension with fatal variceal bleeding	Audiologic/Otolaryngologic; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal	4688793; 9375913; 17160906; 18327255; 19058225; 19508969; 19574260; 20232449; 20607301; 21633164; 21068128; 29891882
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; Variants may modify severity of BBS and related disorders due to variants in other BBS-associated genes; Renal transplant has been described in RHYNS syndrome

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TMEM67 gene.

• Meckel-Gruber syndrome;Familial aplasia of the vermis (300 variants)
• Familial aplasia of the vermis;Meckel-Gruber syndrome (300 variants)
• not provided (185 variants)
• Joubert syndrome 6 (123 variants)
• Meckel syndrome, type 3 (87 variants)
• 6 conditions (81 variants)
• not specified (69 variants)
• Nephronophthisis 11 (68 variants)
• Inborn genetic diseases (33 variants)
• COACH syndrome 1 (17 variants)
• TMEM67-related condition (16 variants)
• Joubert syndrome and related disorders (12 variants)
• TMEM67-Related Disorders (7 variants)
• RHYNS syndrome (7 variants)
• Nephronophthisis (6 variants)
• Meckel-Gruber syndrome (5 variants)
• Joubert syndrome 1 (4 variants)
• Kidney disorder (4 variants)
• 14 conditions (2 variants)
• Enlarged kidney;Multiple renal cysts;Anhydramnios (2 variants)
• Familial aplasia of the vermis (2 variants)
• Nystagmus;Iris coloboma;Generalized hypotonia;Cerebellar vermis hypoplasia (1 variants)
• Bardet-Biedl syndrome 14 (1 variants)
• Ciliopathy (1 variants)
• Spastic ataxia (1 variants)
• Familial aplasia of the vermis;Renal cyst;Oligohydramnios (1 variants)
• Iris coloboma;Nystagmus;Generalized hypotonia;Cerebellar vermis hypoplasia (1 variants)
• Abnormality of the nervous system (1 variants)
• Intellectual disability (1 variants)
• Oligohydramnios;Familial aplasia of the vermis;Renal cyst (1 variants)
• Bardet-Biedl syndrome 14, modifier of (1 variants)
• Nephronophthisis 11;Bardet-Biedl syndrome 14;Joubert syndrome 6;Meckel syndrome, type 3;COACH syndrome 1 (1 variants)
• Joubert syndrome 6;Bardet-Biedl syndrome;COACH syndrome 1 (1 variants)
• Atypical hemolytic-uremic syndrome (1 variants)
• Meckel syndrome, type 3;Bardet-Biedl syndrome 14;Joubert syndrome 6;Nephronophthisis 11;COACH syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TMEM67 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	87	1	95
missense	17	27	297	5	1	347
nonsense	19	6				25
start loss			1			1
frameshift	16	9	1			26
inframe indel		1	5			6
splice donor/acceptor (+/-2bp)	12	14	2			28
splice region	3	4	32	27	3	69
non coding			22	128	40	190
Total	64	57	335	220	42

Highest pathogenic variant AF is 0.000236

Variants in TMEM67

This is a list of pathogenic ClinVar variants found in the TMEM67 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-93754876-TG-T		Familial aplasia of the vermis • Nephronophthisis • Meckel-Gruber syndrome • not specified • TMEM67-related disorder	Conflicting classifications of pathogenicity (Jun 24, 2022)
8-93754882-G-A		not specified	Likely benign (Mar 12, 2018)
8-93754889-G-C		Nephronophthisis 11 • Joubert syndrome 6 • Meckel syndrome, type 3 • TMEM67-related disorder	Benign (Feb 07, 2023)
8-93754911-T-G		not specified	Likely benign (Jul 06, 2017)
8-93754914-C-T		not specified	Uncertain significance (Apr 03, 2023)
8-93754915-A-G		Meckel-Gruber syndrome;Familial aplasia of the vermis	Uncertain significance (Sep 27, 2022)
8-93754917-G-T			Uncertain significance (Sep 16, 2018)
8-93754919-C-T		Familial aplasia of the vermis;Meckel-Gruber syndrome	Uncertain significance (Oct 31, 2022)
8-93754922-C-T		Meckel-Gruber syndrome;Familial aplasia of the vermis • 6 conditions	Uncertain significance (Jun 27, 2022)
8-93754923-G-A		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (Feb 05, 2022)
8-93754927-G-T		Familial aplasia of the vermis;Meckel-Gruber syndrome	Uncertain significance (Jul 08, 2022)
8-93754929-T-G		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Dec 24, 2023)
8-93754932-G-C		Meckel-Gruber syndrome;Familial aplasia of the vermis	Likely benign (May 18, 2021)
8-93754939-G-A		not specified • Familial aplasia of the vermis;Meckel-Gruber syndrome • Joubert syndrome 1 • 6 conditions • TMEM67-related disorder	Conflicting classifications of pathogenicity (Jan 25, 2024)
8-93754942-G-A		Meckel-Gruber syndrome;Familial aplasia of the vermis • Inborn genetic diseases	Uncertain significance (Dec 12, 2023)
8-93754943-C-T		Nephronophthisis 11 • Joubert syndrome 6 • Meckel syndrome, type 3 • Meckel-Gruber syndrome;Familial aplasia of the vermis • 6 conditions	Uncertain significance (Jun 22, 2022)
8-93754945-A-G		Meckel-Gruber syndrome;Familial aplasia of the vermis • 6 conditions	Uncertain significance (Aug 12, 2022)
8-93754946-T-A		Meckel-Gruber syndrome;Familial aplasia of the vermis	Uncertain significance (Aug 24, 2021)
8-93754950-G-A		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Nov 17, 2023)
8-93754950-G-C		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Jan 19, 2023)
8-93754951-G-A		Familial aplasia of the vermis;Meckel-Gruber syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 25, 2024)
8-93754953-T-G		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Aug 10, 2023)
8-93754956-G-T		Meckel-Gruber syndrome;Familial aplasia of the vermis	Uncertain significance (May 17, 2022)
8-93754957-T-A		not specified • 6 conditions • Familial aplasia of the vermis;Meckel-Gruber syndrome	Conflicting classifications of pathogenicity (Sep 12, 2023)
8-93754959-C-T		Familial aplasia of the vermis;Meckel-Gruber syndrome	Likely benign (Dec 12, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TMEM67	protein_coding	protein_coding	ENST00000453321	28	64391

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.07e-24	0.244	125589	0	159	125748	0.000632

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.492	483	514	0.939	0.0000244	6548
Missense in Polyphen		129	153.64	0.83961		2004
Synonymous	1.27	150	171	0.876	0.00000790	1847
Loss of Function	1.92	46	62.3	0.738	0.00000316	740

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000965	0.000963
Ashkenazi Jewish	0.00149	0.00149
East Asian	0.000707	0.000707
Finnish	0.000187	0.000185
European (Non-Finnish)	0.000556	0.000536
Middle Eastern	0.000707	0.000707
South Asian	0.00121	0.00121
Other	0.000993	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for ciliary structure and function. Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). Involved in centrosome migration to the apical cell surface during early ciliogenesis. Involved in the regulation of cilia length and appropriate number through the control of centrosome duplication. Required for cell branching morphology. Essential for endoplasmic reticulum-associated degradation (ERAD) of surfactant protein C (SFTPC). {ECO:0000250, ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:19515853, ECO:0000269|PubMed:19596800, ECO:0000269|PubMed:19815549}.
• Disease: DISEASE: Meckel syndrome 3 (MKS3) [MIM:607361]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:16415887, ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:19466712, ECO:0000269|PubMed:20232449}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 6 (JBTS6) [MIM:610688]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. 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 retinal dystrophy and renal disease. {ECO:0000269|PubMed:17160906, ECO:0000269|PubMed:19508969, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:21633164, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bardet-Biedl syndrome 14 (BBS14) [MIM:615991]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:18327255}. Note=The gene represented in this entry may act as a disease modifier. TMEM67 variations may influence the expression of Bardet-Biedl syndrome in patients who have causative mutations in other genes. Heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, and homozygosity for a truncating mutation of the CEP290 gene has been found in a patient with Bardet-Biedl syndrome 14.; DISEASE: COACH syndrome (COACHS) [MIM:216360]: A disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome and related disorders. Other features, such as coloboma and renal cysts, may be variable. {ECO:0000269|PubMed:19058225, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:28860541}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephronophthisis 11 (NPHP11) [MIM:613550]: A disorder characterized by the association of nephronophthisis with hepatic fibrosis. Nephronophthisis is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Typical clinical features are chronic renal failure, anemia, polyuria, polydipsia, isosthenuria, and growth retardation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. {ECO:0000269|PubMed:19508969}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.191

Intolerance Scores

• loftool: 0.0847
• rvis_EVS: 0.31
• rvis_percentile_EVS: 72.75

Haploinsufficiency Scores

• pHI: 0.0585
• hipred: N
• hipred_score: 0.237
• ghis: 0.490

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.329

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tmem67
• Phenotype: cellular phenotype; craniofacial phenotype; growth/size/body region phenotype; liver/biliary system phenotype; renal/urinary system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); embryo phenotype

Zebrafish Information Network

• Gene name: tmem67
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: hydrocephalic

Gene ontology

• Biological process: negative regulation of centrosome duplication;ubiquitin-dependent ERAD pathway;cilium assembly;ciliary basal body-plasma membrane docking
• Cellular component: endoplasmic reticulum membrane;centrosome;integral component of membrane;cytoplasmic vesicle membrane;ciliary transition zone;MKS complex;ciliary membrane
• Molecular function: protein binding;filamin binding;unfolded protein binding