TMCO1

protein-coding

transmembrane and coiled-coil domains 1

Gene summary

This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

Previous symbols:

TMCC4

MANE transcript

NM_019026.6

Inheritance

ClinVar variants

P:17U:29B:5

Top phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr1:165,724,293-165,827,755

External References & Databases

Ensembl (ENSG00000143183)

Transcript & Mutation Effects

hg38 • Region Span ~103.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800436

Submitter: PanelApp Australia

cerebrofaciothoracic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008952

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

cerebrofaciothoracic dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008952

Submitter: Illumina

craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800436

Submitter: G2P

cerebrofaciothoracic dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008952

Submitter: Ambry Genetics

craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800436

Submitter: Labcorp Genetics (formerly Invitae)

cerebrofaciothoracic dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008952

Submitter: Orphanet

Clinical Genomic Database (CGD)

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1AR

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Renal

Intervention: Renal

Rationale: Individuals have been described with renal anomalies and/or vesicoureteral reflux, and surveillance and management may be helpful to preserve renal function

Refs: 17351359; 20018682; 23320496; 24194475; 30556256; 31102500

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMCO1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 38

Inborn genetic diseasesTotal: 19

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1Total: 12

TMCO1-related disorderTotal: 3

Premature ovarian failureTotal: 1

Cerebro-facio-thoracic dysplasiaTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019026.6. 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			1 clinvar	5 clinvar		6
missense	1 clinvar	1 clinvar	25 clinvar			27
nonsense	4 clinvar	3 clinvar				7
start loss						0
frameshift	1 clinvar	4 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	2 clinvar			5
Total	7	10	29	5	0	51

Highest pathogenic variant AF is 0.00025544464

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019026.6	RefSeq	NP_061899.3	7	MANE Select
ENST00000367881.11	Ensembl	ENSP00000356856.6	7	MANE Select
NM_001256164.1	RefSeq	NP_001243093.1	7	Standard
NM_001256165.1	RefSeq	NP_001243094.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ER overload response
endoplasmic reticulum calcium ion homeostasis
calcium ion transmembrane transport

Molecular Function

calcium channel activity

Cellular Component

Golgi membrane
endoplasmic reticulum
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367881
Coding exons: 7
Length: 100961
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 79
Defined: 125747
p: 0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.03	96	129	0.745	0.00000626	1525
Missense (PolyPhen)		21	31.521	0.66621		419
Synonymous	-0.0660	46	45.4	1.01	0.00000220	483
Loss of Function	0.438	15	16.9	0.885	0.00000110	160

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00037	rare
Latino/Admixed American	0.00030	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000097	0.000092	rare
European (Non-Finnish)	0.00044	0.00044	rare
South Asian	0.00024	0.00023	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-selective channel required to prevent calcium stores from overfilling, thereby playing a key role in calcium homeostasis (PubMed:27212239). In response to endoplasmic reticulum overloading, assembles into a homotetramer, forming a functional calcium-selective channel, regulating the calcium content in endoplasmic reticulum store (PubMed:27212239). {ECO:0000269|PubMed:27212239}.;
Disease: DISEASE: Glaucoma, primary open angle (POAG) [MIM:137760]: A complex and genetically heterogeneous ocular disorder characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. In some cases, POAG shows digenic inheritance involving mutations in CYP1B1 and MYOC genes. {ECO:0000269|PubMed:21532571, ECO:0000269|PubMed:22714896}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

RVIS EVS: 0.06
RVIS percentile EVS: 58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.476

Gene Damage Prediction

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