TMEM70

protein-coding

transmembrane protein 70, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene likely encodes a mitochondrial membrane protein. The encoded protein may play a role in biogenesis of mitochondrial ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MANE transcript

NM_017866.6

Inheritance

ClinVar variants

P:40U:140B:108

Top phenotype

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr8:73,972,437-73,982,783

External References & Databases

Ensembl (ENSG00000175606)

Transcript & Mutation Effects

hg38 • Region Span ~10.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013546

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013546

Submitter: PanelApp Australia

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013546

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TMEM70* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The *TMEM70* gene encodes a mitochondrial respiratory chain complex V assembly factor that likely works in complex I assembly (PMIDs: 32275929, 33753518), as well. The *TMEM70* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18953340). While various names have been given to the constellation of features seen in those with *TMEM70*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TMEM70* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (two splice site, two nonsense, one frameshift) identified in eight individuals from two publications (PMIDs: 18953340, 21147908). More evidence is available in the literature but the maximum score for genetic evidence (12 pts.) has been reached. The majority of cases reported had nonsense or splice variants. Affected individuals typically presented in utero to shortly after birth and outcomes varied from death in the first days of life to still being alive at the time of report in their 20s. Affected individuals had variable features including microcephaly, developmental delay, episodic encephalopathy with febrile illness, hypotonia, hypertrophic cardiomyopathy, persistent pulmonary arterial hypertension, hepatopathy, short stature, and cataract; at least one report included an individual with normal cognitive abilities. Brain imaging in affected individuals ranged from normal to hypoplastic corpus callosum, cerebellar atrophy, and cortical atrophy; and metabolic screening labs variably showed lactic acidosis, increased CSF lactate, and lactate excretion in urine; metabolic acidosis; hyperammonemia; and 3MGA. Other features seen in affected individuals include oligohydramnios, hypospadias, cryptorchidism, and dysmorphic features (high forehead, low set ears, long philtrum, broad nasal bridge, thin lips). The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, rescue in patient cells, knock-out mouse model, and rescue in a knock-out rat model (PMIDs: 24740313, 21945727, 28173120, 35203486). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 16, 2022 (SOP Version 8).

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013546

Submitter: G2P

Clinical Genomic Database (CGD)

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

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

Refs: 18953340; 21147908; 24485043

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM70 variants in ClinVar

9 Conditions Cataloged

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2Total: 292

not providedTotal: 41

Inborn genetic diseasesTotal: 41

not specifiedTotal: 27

TMEM70-related disorderTotal: 12

Autosomal recessive diseaseTotal: 2

Neurodevelopmental disorderTotal: 1

Mitochondrial proton-transporting ATP synthase complex deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017866.6. 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			2 clinvar	94 clinvar		96
missense		3 clinvar	131 clinvar	13 clinvar	1 clinvar	148
nonsense	4 clinvar	2 clinvar	3 clinvar			9
start loss		1 clinvar	1 clinvar			2
frameshift	10 clinvar	14 clinvar	3 clinvar			27
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar				6
Total	15	25	140	107	1	288

Highest pathogenic variant AF is 0.00015248041

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017866.6	RefSeq	NP_060336.3	3	MANE Select
ENST00000312184.6	Ensembl	ENSP00000312599.5	3	MANE Select
NM_001040613.3	RefSeq	NP_001035703.1	2	Standard
ENST00000416961.6	Ensembl	ENSP00000407695.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial proton-transporting ATP synthase complex assembly

Molecular Function

molecular_function

Cellular Component

nucleoplasm
mitochondrion
mitochondrial inner membrane
integral component of mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312184
Coding exons: 3
Length: 10347
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125744
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.129	139	143	0.970	0.00000724	1652
Missense (PolyPhen)		33	41.227	0.80046		496
Synonymous	-0.552	65	59.6	1.09	0.00000297	547
Loss of Function	1.75	4	9.95	0.402	6.48e-7	98

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in biogenesis of mitochondrial ATP synthase. {ECO:0000269|PubMed:18953340, ECO:0000269|PubMed:20937241}.;
Disease: DISEASE: Mitochondrial complex V deficiency, nuclear 2 (MC5DN2) [MIM:614052]: A mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid. {ECO:0000269|PubMed:18953340, ECO:0000269|PubMed:22986587}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0543

Intolerance Scores

LoFtool: 0.696
RVIS EVS: 1.06
RVIS percentile EVS: 91.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.131

Gene Damage Prediction

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