THBD

thrombomodulin, the group of CD molecules|C-type lectin domain containing

Basic information

Region (hg38): 20:23045633-23049672

Links

ENSG00000178726 ∙ NCBI:7056 ∙ OMIM:188040 ∙ HGNC:11784 ∙ Uniprot:P07204 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombomodulin-related bleeding disorder (Strong), mode of inheritance: AD
• thrombomodulin-related bleeding disorder (Supportive), mode of inheritance: AD
• atypical hemolytic-uremic syndrome with thrombomodulin anomaly (Strong), mode of inheritance: AD
• thrombomodulin-related bleeding disorder (Limited), mode of inheritance: Unknown
• thrombomodulin-related bleeding disorder (Moderate), mode of inheritance: AD
• thrombomodulin-related bleeding disorder (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thrombophilia due to thrombomodulin defect; Hemolytic uremic syndrome, atypical, susceptibility to, 6	AD	Hematologic; Pharmacogenomic; Renal	In Thrombophilia due to thrombomodulin defect, surveillance, preventive measures, and treatment of thrombophilia may reduce morbidity; In Hemolytic-uremic syndrome, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy), as well as decision to perform renal transplant, may be dictated by genetic diagnosis, and certain agents/precipitating factors should be avoided (eg, certain medications)	Hematologic; Renal	7811989; 9843165; 10460600; 11552992; 12139752; 11986219; 19625716; 20301541; 20595690; 22036808
The evidence for the causality of the reported variants as relates to thrombophilia is unclear

ClinVar

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

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the THBD 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			17	95	7	119
missense			229	6	3	238
nonsense		1	3			4
start loss						0
frameshift		2	2			4
inframe indel			3			3
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding			21	4	22	47
Total	0	3	275	105	32

Variants in THBD

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

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

Position	Type	Phenotype	Significance	ClinVar
20-23045634-G-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 13, 2018)
20-23045648-G-T		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 13, 2018)
20-23045784-A-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 13, 2018)
20-23045859-C-T		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23045908-C-T		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23045932-C-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046007-A-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 13, 2018)
20-23046088-G-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046215-C-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23046258-C-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046272-G-C		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046308-G-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Conflicting classifications of pathogenicity (May 01, 2022)
20-23046462-G-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046506-C-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23046538-C-T		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 13, 2018)
20-23046606-G-C		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23046624-T-C		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 12, 2018)
20-23046673-T-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046766-G-T		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)
20-23046776-T-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23046833-C-CA		Atypical hemolytic-uremic syndrome	Uncertain significance (Jun 14, 2016)
20-23046984-T-C		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23047002-C-G		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Apr 27, 2017)
20-23047018-T-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Benign (Jan 12, 2018)
20-23047114-G-A		Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
THBD	protein_coding	protein_coding	ENST00000377103	1	4109

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0538	0.928	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.602	299	330	0.907	0.0000178	3620
Missense in Polyphen		67	98.363	0.68115		1201
Synonymous	-1.52	175	151	1.16	0.00000966	1181
Loss of Function	2.06	4	11.6	0.346	5.06e-7	108

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: Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
• Disease: DISEASE: Thrombophilia due to thrombomodulin defect (THPH12) [MIM:614486]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:12139752, ECO:0000269|PubMed:7811989, ECO:0000269|PubMed:9198186}. Note=The disease may be caused by mutations affecting the gene represented in this entry. The role of thrombomodulin in thrombosis is controversial. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis.; DISEASE: Hemolytic uremic syndrome atypical 6 (AHUS6) [MIM:612926]: An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. {ECO:0000269|PubMed:19625716, ECO:0000269|PubMed:20513133}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Vitamin D Receptor Pathway;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Dengue-2 Interactions with Complement and Coagulation Cascades;Complement and Coagulation Cascades;Cell surface interactions at the vascular wall;Hemostasis;Common Pathway of Fibrin Clot Formation;Formation of Fibrin Clot (Clotting Cascade);Validated transcriptional targets of AP1 family members Fra1 and Fra2 (Consensus)

Recessive Scores

• pRec: 0.372

Haploinsufficiency Scores

• pHI: 0.226

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.449

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Thbd
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; embryo phenotype; renal/urinary system phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; reproductive system 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); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype

Gene ontology

• Biological process: female pregnancy;blood coagulation;response to X-ray;negative regulation of platelet activation;negative regulation of blood coagulation;response to lipopolysaccharide;response to cAMP;negative regulation of fibrinolysis
• Cellular component: extracellular space;vacuolar membrane;plasma membrane;integral component of plasma membrane;cell surface;apicolateral plasma membrane
• Molecular function: transmembrane signaling receptor activity;calcium ion binding;protein binding;signaling receptor activity