MPL

MPL proto-oncogene, thrombopoietin receptor, the group of CD molecules|Fibronectin type III domain containing

Basic information

Region (hg38): 1:43337818-43354466

Links

ENSG00000117400 ∙ NCBI:4352 ∙ OMIM:159530 ∙ HGNC:7217 ∙ Uniprot:P40238 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombocythemia 2 (Strong), mode of inheritance: AD
• thrombocythemia 2 (Definitive), mode of inheritance: AD
• congenital amegakaryocytic thrombocytopenia (Supportive), mode of inheritance: AR
• familial thrombocytosis (Supportive), mode of inheritance: AD
• hereditary isolated aplastic anemia (Supportive), mode of inheritance: AD
• thrombocythemia 2 (Strong), mode of inheritance: AD
• congenital amegakaryocytic thrombocytopenia (Definitive), mode of inheritance: AR
• congenital amegakaryocytic thrombocytopenia (Strong), mode of inheritance: AR
• thrombocythemia 2 (Definitive), mode of inheritance: AD
• congenital amegakaryocytic thrombocytopenia 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thrombocythemia 2; Amegakaryocytic thrombocytopenia, congenital, 1	AD/AR	Hematologic; Oncologic	For Thrombocythemia 2, manifestations may include thrombotic/hemorrhagic episodes, as well as leukemic transformation, and surveillance and prompt treatment may be beneficial; For Amegakaryocytic thrombocytopenia, individuals may have findings such as severe bleeding complications, and platelet transfusion can be beneficial; Effective SCT has been described	Hematologic; Oncologic	9029014; 10077649; 11133753; 14764528; 15269348; 16351641; 17054430

ClinVar

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

• Essential thrombocythemia;Congenital amegakaryocytic thrombocytopenia (51 variants)
• Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia (27 variants)
• Congenital amegakaryocytic thrombocytopenia (17 variants)
• not provided (7 variants)
• not specified (5 variants)
• Congenital amegakaryocytic thrombocytopenia 1 (3 variants)
• Primary myelofibrosis (2 variants)
• Thrombocythemia 2;Congenital amegakaryocytic thrombocytopenia;Primary myelofibrosis (2 variants)
• Thrombocytopenia (1 variants)
• MPL-related disorder (1 variants)
• Congenital amegakaryocytic thrombocytopenia;Thrombocythemia 2;Primary myelofibrosis (1 variants)
• Thrombocythemia 2 (1 variants)
• Thrombocythemia 1 (1 variants)
• Congenital amegakaryocytic thrombocytopenia;Primary myelofibrosis;Thrombocythemia 2 (1 variants)
• Myeloproliferative neoplasm (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MPL 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			2	206		208
missense	7	14	139	6	1	167
nonsense	34	23	1			58
start loss						0
frameshift	41	17	1			59
inframe indel	1		1			2
splice donor/acceptor (+/-2bp)	2	19	1	1		23
splice region			3	35	2	40
non coding			25	106	7	138
Total	85	73	170	319	8

Highest pathogenic variant AF is 0.000263

Variants in MPL

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

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

Position	Type	Phenotype	Significance	ClinVar
1-43337836-A-C		Congenital amegakaryocytic thrombocytopenia	Uncertain significance (Jan 12, 2018)
1-43337854-C-T		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Jan 09, 2024)
1-43337857-C-G		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Oct 13, 2022)
1-43337858-T-C		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Uncertain significance (Sep 11, 2023)
1-43337859-G-A		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Pathogenic (Nov 02, 2023)
1-43337860-G-A		Congenital amegakaryocytic thrombocytopenia	Uncertain significance (Aug 16, 2021)
1-43337870-A-G		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Uncertain significance (Jan 26, 2022)
1-43337875-C-T		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Nov 20, 2023)
1-43337890-C-T		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Aug 18, 2021)
1-43337893-G-GTATAAGAGACA		Congenital amegakaryocytic thrombocytopenia	Likely pathogenic (Jan 24, 2022)
1-43337897-C-T		Congenital amegakaryocytic thrombocytopenia	Uncertain significance (Jan 12, 2018)
1-43337899-T-G		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Dec 16, 2020)
1-43337900-CA-C		Congenital amegakaryocytic thrombocytopenia	Likely pathogenic (Jan 28, 2022)
1-43337905-C-A		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia • Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 24, 2023)
1-43337917-C-A		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Oct 04, 2023)
1-43337928-G-A		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely pathogenic (Dec 26, 2022)
1-43337928-G-T		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely pathogenic (Dec 14, 2020)
1-43337929-T-A		not specified • Congenital amegakaryocytic thrombocytopenia • Congenital amegakaryocytic thrombocytopenia;Primary myelofibrosis;Thrombocythemia 2 • MPL-related disorder • Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia • Thrombocytopenia • Primary myelofibrosis	Pathogenic/Likely pathogenic (Jan 29, 2024)
1-43337934-T-C		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Feb 05, 2020)
1-43337935-G-C		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Jun 11, 2022)
1-43337936-C-G		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Feb 22, 2023)
1-43337936-C-T		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Dec 12, 2023)
1-43337937-A-C		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Nov 04, 2023)
1-43337942-G-A		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Jun 28, 2023)
1-43337942-G-C		Congenital amegakaryocytic thrombocytopenia;Essential thrombocythemia	Likely benign (Aug 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MPL	protein_coding	protein_coding	ENST00000372470	12	14966

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.07e-9	0.997	125546	0	202	125748	0.000804

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.395	311	331	0.939	0.0000181	4043
Missense in Polyphen		83	88.638	0.93639		1120
Synonymous	2.42	101	137	0.737	0.00000719	1313
Loss of Function	2.72	20	38.1	0.525	0.00000224	362

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000543	0.000543
Ashkenazi Jewish	0.00834	0.00817
East Asian	0.000598	0.000598
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000621	0.000615
Middle Eastern	0.000598	0.000598
South Asian	0.000621	0.000621
Other	0.000999	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for thrombopoietin that acts as a primary regulator of megakaryopoiesis and platelet production. May represent a regulatory molecule specific for TPO-R-dependent immune responses. {ECO:0000250|UniProtKB:Q08351}.
• Disease: DISEASE: Congenital amegakaryocytic thrombocytopenia (CAMT) [MIM:604498]: Disease characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies. {ECO:0000269|PubMed:16470591, ECO:0000269|PubMed:25538044}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombocythemia 2 (THCYT2) [MIM:601977]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:14764528, ECO:0000269|PubMed:19483125, ECO:0000269|PubMed:23441089, ECO:0000269|PubMed:25538044}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450]: A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly. {ECO:0000269|PubMed:16834459, ECO:0000269|PubMed:16868251}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Jak-STAT signaling pathway - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);JAK-STAT-Core;JAK STAT MolecularVariation 1;Platelet Aggregation (Plug Formation);Platelet activation, signaling and aggregation;tpo signaling pathway;JAK STAT MolecularVariation 2;Hemostasis;JAK STAT pathway and regulation;TPO signaling (Consensus)

Recessive Scores

• pRec: 0.282

Intolerance Scores

• loftool: 0.343
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.82

Haploinsufficiency Scores

• pHI: 0.710
• hipred: Y
• hipred_score: 0.598
• ghis: 0.466

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.932

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mpl
• Phenotype: growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; embryo phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: mpl
• Affected structure: thromboblast
• Phenotype tag: abnormal
• Phenotype quality: decreased occurrence

Gene ontology

• Biological process: neutrophil homeostasis;cell surface receptor signaling pathway;cell population proliferation;monocyte homeostasis;thrombopoietin-mediated signaling pathway;positive regulation of lymphocyte proliferation;platelet aggregation;cellular response to hypoxia;positive regulation of platelet formation;eosinophil homeostasis;basophil homeostasis
• Cellular component: Golgi apparatus;plasma membrane;integral component of plasma membrane;cell surface;neuron projection;neuronal cell body
• Molecular function: transmembrane signaling receptor activity;protein binding;thrombopoietin receptor activity