TIMM8A

translocase of inner mitochondrial membrane 8A

Basic information

Region (hg38): X:101345660-101348742

Previous symbols: [ "DFN1" ]

Links

ENSG00000126953 ∙ NCBI:1678 ∙ OMIM:300356 ∙ HGNC:11817 ∙ Uniprot:O60220 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• deafness dystonia syndrome (Strong), mode of inheritance: XL
• deafness dystonia syndrome (Strong), mode of inheritance: XL
• deafness dystonia syndrome (Supportive), mode of inheritance: XL
• deafness dystonia syndrome (Strong), mode of inheritance: XL
• deafness dystonia syndrome (Strong), mode of inheritance: XL
• deafness dystonia syndrome (Strong), mode of inheritance: XL
• deafness dystonia syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Opticoacoustic nerve atrophy with dementia; Jensen syndrome; Mohr-Tranebjaerg syndrome	XL	Audiologic/Otolaryngologic; Pharmacogenomic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Aminoglycosides should be avoided	Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Ophthalmologic	5649; 7643352; 8841189; 10878669; 11803487; 11405816; 18952432
Deafness may be postlingual in many individuals with certain TIMM8A-related conditions

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TIMM8A gene.

• not provided (33 variants)
• not specified (7 variants)
• Deafness dystonia syndrome (6 variants)
• Inborn genetic diseases (5 variants)
• Auditory neuropathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TIMM8A 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			1	13	1	15
missense		2	5	1		8
nonsense						0
start loss						0
frameshift	3					3
inframe indel						0
splice donor/acceptor (+/-2bp)	1		1			2
splice region					1	1
non coding			2	5	5	12
Total	4	2	9	19	6

Variants in TIMM8A

This is a list of pathogenic ClinVar variants found in the TIMM8A region.

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

Position	Type	Phenotype	Significance	ClinVar
X-101345993-G-GATC		Deafness dystonia syndrome	Benign (Feb 06, 2003)
X-101346511-G-T		not specified	Uncertain significance (May 23, 2016)
X-101346523-A-G			Likely benign (May 27, 2022)
X-101346526-T-C			Likely benign (Jan 08, 2024)
X-101346535-T-C			Benign (Jun 13, 2022)
X-101346541-G-A		not specified	Likely benign (Nov 22, 2017)
X-101346542-G-A			Benign/Likely benign (Oct 22, 2023)
X-101346555-G-A		Deafness dystonia syndrome	Pathogenic (Jun 01, 2001)
X-101346560-A-AATTG		Deafness dystonia syndrome	Likely pathogenic (-)
X-101346567-A-C			Uncertain significance (Jul 06, 2022)
X-101346567-A-G			Uncertain significance (Nov 28, 2023)
X-101346568-C-T			Likely benign (Jul 26, 2022)
X-101346570-G-A		Deafness dystonia syndrome	Pathogenic (-)
X-101346574-T-G			Likely benign (Apr 14, 2023)
X-101346577-A-G		Inborn genetic diseases	Benign/Likely benign (Jan 03, 2024)
X-101346587-C-T			Uncertain significance (Jun 04, 2023)
X-101346594-C-T			Conflicting classifications of pathogenicity (Nov 19, 2021)
X-101346595-G-C		Deafness dystonia syndrome	Likely pathogenic (Nov 06, 2020)
X-101346611-GC-G		Deafness dystonia syndrome	Pathogenic (May 04, 2022)
X-101346625-G-A		Inborn genetic diseases	Likely benign (Mar 16, 2020)
X-101346635-GGCCCAGGCTT-G		Deafness dystonia syndrome	Pathogenic (May 01, 2023)
X-101346640-A-G			Likely benign (Jun 29, 2023)
X-101346657-TCTC-T		Auditory neuropathy	Conflicting classifications of pathogenicity (Dec 22, 2023)
X-101346661-C-A			Pathogenic (Oct 23, 2020)
X-101346662-T-C			Uncertain significance (Aug 23, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TIMM8A	protein_coding	protein_coding	ENST00000372902	2	3536

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.652	0.325	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.15	17	36.6	0.465	0.00000274	644
Missense in Polyphen		0	5.3661	0		125
Synonymous	-0.643	17	13.9	1.22	0.00000100	181
Loss of Function	1.71	0	3.41	0.00	2.74e-7	44

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. Probably necessary for normal neurologic development. {ECO:0000269|PubMed:11489896, ECO:0000269|PubMed:15254020}.
• Disease: DISEASE: Mohr-Tranebjaerg syndrome (MTS) [MIM:304700]: An X-linked recessive disorder characterized by postlingual sensorineural deafness with onset in early childhood, dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. {ECO:0000269|PubMed:10878669, ECO:0000269|PubMed:11803487, ECO:0000269|PubMed:11875042, ECO:0000269|PubMed:11956200}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Metabolism of proteins;Mitochondrial protein import (Consensus)

Recessive Scores

• pRec: 0.250

Intolerance Scores

• rvis_EVS: 0.04
• rvis_percentile_EVS: 56.25

Haploinsufficiency Scores

• pHI: 0.363
• hipred: Y
• hipred_score: 0.765
• ghis: 0.563

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Mouse Genome Informatics

• Gene name: Timm8a1

Gene ontology

• Biological process: nervous system development;chaperone-mediated protein transport
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial intermembrane space
• Molecular function: protein binding;metal ion binding