TFAM

protein-coding

transcription factor A, mitochondrial

Gene summary

This gene encodes a key mitochondrial transcription factor containing two high mobility group motifs. The encoded protein also functions in mitochondrial DNA replication and repair. Sequence polymorphisms in this gene are associated with Alzheimer's and Parkinson's diseases. There are pseudogenes for this gene on chromosomes 6, 7, and 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

Previous symbols:

TCF6
TCF6L2

MANE transcript

NM_003201.3

Inheritance

ClinVar variants

P:2U:41B:19

Top phenotype

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr10:58,385,345-58,399,220

External References & Databases

Ensembl (ENSG00000108064)

Transcript & Mutation Effects

hg38 • Region Span ~13.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome 15 (hepatocerebral type)LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014943

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 15 (hepatocerebral type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014943

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 15 (hepatocerebral type)LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014943

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)AR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic

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: 27448789

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFAM variants in ClinVar

6 Conditions Cataloged

not providedTotal: 61

not specifiedTotal: 26

TFAM-related disorderTotal: 5

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)Total: 4

Premature ovarian insufficiencyTotal: 1

Sensorineural hearing loss disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003201.3. 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				12 clinvar	1 clinvar	13
missense		1 clinvar	39 clinvar	6 clinvar		46
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	2	41	18	1	62

Highest pathogenic variant AF is 0.004609181

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003201.3	RefSeq	NP_003192.1	7	MANE Select
ENST00000487519.6	Ensembl	ENSP00000420588.1	7	MANE Select
NM_001270782.2	RefSeq	NP_001257711.1	6	Standard
ENST00000373895.7	Ensembl	ENSP00000363002.3	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Huntington,s disease - Homo sapiens (human)
Apelin signaling pathway - Homo sapiens (human)
Energy Metabolism
Mitochondrial biogenesis
NAD metabolism, sirtuins and aging

Biological Process

mitochondrial transcription
transcription initiation from mitochondrial promoter
mitochondrion organization
mitochondrial respiratory chain complex assembly
positive regulation of transcription, DNA-templated

Molecular Function

mitochondrial promoter sequence-specific DNA binding
transcription coactivator binding
chromatin binding
DNA-binding transcription factor activity
RNA binding

Cellular Component

nucleus
mitochondrion
mitochondrial matrix
cytosol
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000487519
Coding exons: 7
Length: 14200
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125743
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.11	96	132	0.728	0.00000707	1585
Missense (PolyPhen)		14	36.589	0.38262		401
Synonymous	-0.371	46	42.9	1.07	0.00000223	438
Loss of Function	2.63	4	15.0	0.267	6.85e-7	185

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation (PubMed:29445193). Required for accurate and efficient promoter recognition by the mitochondrial RNA polymerase. Promotes transcription initiation from the HSP1 and the light strand promoter by binding immediately upstream of transcriptional start sites. Is able to unwind DNA. Bends the mitochondrial light strand promoter DNA into a U-turn shape via its HMG boxes. Required for maintenance of normal levels of mitochondrial DNA. May play a role in organizing and compacting mitochondrial DNA. {ECO:0000269|PubMed:1737790, ECO:0000269|PubMed:19304746, ECO:0000269|PubMed:20410300, ECO:0000269|PubMed:22037171, ECO:0000269|PubMed:22037172, ECO:0000269|PubMed:22841477, ECO:0000269|PubMed:29445193}.;
Disease: DISEASE: Mitochondrial DNA depletion syndrome 15, hepatocerebral type (MTDPS15) [MIM:617156]: An autosomal recessive mitochondrial disorder characterized by severe intrauterine growth restriction, neonatal-onset hypoglycemia and liver dysfunction, mitochondrial DNA depletion in liver and skeletal muscle, and abnormal mitochondrial morphology observed in skeletal muscle. Hepatic pathology includes cirrhosis, steatosis and cholestasis. Progression to liver failure and death is rapid with no evidence of neurological impairment or other organ involvement. {ECO:0000269|PubMed:27448789}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.202

Intolerance Scores

LoFtool: 0.492
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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