TMEM106B

protein-coding

transmembrane protein 106B

Gene summary

Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy 16. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001134232.2

Inheritance

AD, AR

ClinVar variants

P:2U:74B:33

Top phenotype

Leukodystrophy, hypomyelinating 16

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr7:12,211,270-12,243,367

External References & Databases

Ensembl (ENSG00000106460)

Transcript & Mutation Effects

hg38 • Region Span ~32.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy, hypomyelinating, 16STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054791

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 16STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054791

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 16DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054791

Submitter: ClinGen

TMEM106B Hypomyelinating Leukodystrophy 16, autosomal dominant Preferred name: TMEM106B-related hypomyelinating leukodystrophy The TMEM106B gene encodes for a glycoprotein that is located in the membrane of late endosomes and lysosomes (PMID: 37563705). This protein is thought to be involved in endolysosome sorting and fusion, retrograde transport of lysosomes, lysosome acidification and protein degradation (PMID: 37563705). A heterozygous variant in TMEM106B was first reported in relation to autosomal dominant hypomyelinating leukodystrophy type 16 (HLD16) in 2017 (Simons et al., PMID: 29186371). Affected individuals present with nystagmus, saccadic pursuit, poor feeding, hypotonia, hypertonia, delayed development (primarily motor), intellectual disability, learning differences, gait ataxia, intention tremor, dysarthria, dystonia, dysmetria, hyperreflexia, pyramidal signs, hypomyelination, and thin corpus callosum. Onset occurs in infancy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a consistent phenotype and no difference in molecular mechanisms or inheritance pattern; therefore, the single disease entity of HLD16 has been maintained. A single recurrent missense variant has been reported in 10 probands across 7 publications (PMIDs: 29186371, 29444210, 32595021, 36046422, 36950148, 37077564, 38008000). All variants occurred de novo in the affected individual, except one case in which the variant was inherited from a mosaic parent. The mechanism of pathogenicity is unknown although gain-of-function or dominant-negative mechanisms have been suggested (PMID: 30643851). This gene-disease relationship is also supported by experimental evidence. A knockout mouse demonstrated mild motor coordination issues as well as myelination defects (PMID: 32572497). Protein interaction studies show that the protein encoded by the VPS11 gene, which has been implicated in a different hypomyelinating leukodystrophy, interacts with TMEM106B cytoplasmic domain (PMID: 25066864). In summary, there is definitive evidence supporting the relationship between TMEM106B and autosomal dominant hypomyelinating leukodystrophy 16, also known as TMEM106B-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date June 23, 2025 (SOP Version 11).

leukodystrophy, hypomyelinating, 16LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0054791

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 16STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054791

Submitter: G2P

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating 16AR

Manifestation: 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: 29186371; 29444210

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM106B variants in ClinVar

7 Conditions Cataloged

not providedTotal: 82

Inborn genetic diseasesTotal: 31

Leukodystrophy, hypomyelinating, 16Total: 9

not specifiedTotal: 4

TMEM106B-related disorderTotal: 4

Vascular dementiaTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134232.2. 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	17 clinvar	3 clinvar	22
missense	1 clinvar	1 clinvar	62 clinvar	11 clinvar	2 clinvar	77
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	1	1	74	28	5	109

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134232.2	RefSeq	NP_001127704.1	7	MANE Select
ENST00000396668.8	Ensembl	ENSP00000379902.3	7	MANE Select
NM_018374.4	RefSeq	NP_060844.2	7	Standard
ENST00000396667.7	Ensembl	ENSP00000379901.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

lysosome organization
lysosomal transport
lysosome localization
dendrite morphogenesis
positive regulation of dendrite development

Molecular Function

molecular_function
protein binding

Cellular Component

lysosome
lysosomal membrane
endosome
integral component of membrane
late endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396667
Coding exons: 7
Length: 32127
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125729
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.917	115	146	0.787	0.00000720	1794
Missense (PolyPhen)		31	60.649	0.51114		754
Synonymous	-0.617	57	51.4	1.11	0.00000259	517
Loss of Function	2.55	3	12.8	0.234	6.31e-7	175

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6. May act by inhibiting retrograde transport of lysosomes along dendrites. Required for dendrite branching. {ECO:0000269|PubMed:23136129, ECO:0000269|PubMed:24357581}.;
Disease: DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) [MIM:105550]: An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:24385136, ECO:0000269|PubMed:24442578, ECO:0000303|PubMed:24488309}. Note=The gene represented in this entry acts as a disease modifier.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.519
RVIS EVS: 0.33
RVIS percentile EVS: 73.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.148

Gene Damage Prediction

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