GeneBe

TYROBP

protein-coding

transmembrane immune signaling adaptor TYROBP

Gene summary

This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The encoded protein may associate with the killer-cell inhibitory receptor (KIR) family of membrane glycoproteins and may act as an activating signal transduction element. This protein may bind zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) and spleen tyrosine kinase (SYK) and play a role in signal transduction, bone modeling, brain myelination, and inflammation. Mutations within this gene have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease. Its putative receptor, triggering receptor expressed on myeloid cells 2 (TREM2), also causes PLOSL. Multiple alternative transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Mar 2010]

Previous symbols:
  • PLOSL

MANE transcript

NM_003332.4

Inheritance

AR

ClinVar variants

P:10U:43B:31

Top phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (Nasu-Hakola disease)

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr19:35,904,401-35,908,295

External References & Databases

Ensembl (ENSG00000011600)NCBI Gene (7305)OMIM (604142)HGNC:12449GenCCUniProt (O43914)AlphaFoldClinVar (TYROBP)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020749

Submitter: Labcorp Genetics (formerly Invitae)

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020749

Submitter: Genomics England PanelApp

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020749

Submitter: Ambry Genetics

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009092

Submitter: Orphanet

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020749

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (Nasu-Hakola disease)AR

Manifestation: 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: 10888890; 12370476; 15049507; 15883308; 17125796; 22082900Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TYROBP variants in ClinVar

14 Conditions Cataloged
not providedTotal: 87
Inborn genetic diseasesTotal: 22
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1Total: 17
not specifiedTotal: 9
TYROBP-related disorderTotal: 7
Parkinsonian disorderTotal: 1
Memory impairmentTotal: 1
Frontotemporal cerebral atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003332.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
21
clinvar
 22
missense
1
clinvar
37
clinvar
9
clinvar
1
clinvar
 48
nonsense
2
clinvar
1
clinvar
 3
start loss
2
clinvar
1
clinvar
 3
frameshift
1
clinvar
2
clinvar
1
clinvar
 4
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
 4
Total644330184

Highest pathogenic variant AF is 0.00009046633

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003332.4RefSeqNP_003323.15MANE Select
ENST00000262629.9EnsemblENSP00000262629.35MANE Select
NM_001173514.2RefSeqNP_001166985.14Standard
NM_001173515.2RefSeqNP_001166986.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Natural killer cell mediated cytotoxicity - Homo sapiens (human)
  • Osteoclast differentiation - Homo sapiens (human)
  • Microglia Pathogen Phagocytosis Pathway
  • TYROBP Causal Network
  • Fibrin Complement Receptor 3 Signaling Pathway

Biological Process

  • macrophage activation involved in immune response
  • cellular defense response
  • signal transduction
  • integrin-mediated signaling pathway
  • osteoclast differentiation

Molecular Function

  • signaling receptor binding
  • protein binding
  • identical protein binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • cell surface
  • secretory granule membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000262629
Coding exons
5
Length
3895
Individuals with no LoFs
125638
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125660
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.3247971.31.110.00000460694
Missense (PolyPhen)1323.5980.55089278
Synonymous-0.8434134.71.180.00000239256
Loss of Function1.7126.840.2923.79e-767

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000630.000058rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.000160.00016rare
Finnish0.000540.00051rare
European (Non-Finnish)0.0000270.000026rare
South Asian00.0absent
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Non-covalently associates with activating receptors of the CD300 family. Cross-linking of CD300-TYROBP complexes results in cellular activation. Involved for instance in neutrophil activation mediated by integrin.;
Disease
DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) [MIM:221770]: Recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10(-6) in the Finns. {ECO:0000269|PubMed:10888890, ECO:0000269|PubMed:12370476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.311

Intolerance Scores

LoFtool
0.185
RVIS EVS
0.24
RVIS percentile EVS
68.98

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.510

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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