UNC13D

unc-13 homolog D, the group of UNC13 homologs

Basic information

Region (hg38): 17:75827225-75844785

Links

ENSG00000092929

∙ NCBI:201294 ∙ OMIM:608897 ∙ HGNC:23147 ∙ Uniprot:Q70J99 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

familial hemophagocytic lymphohistiocytosis 3 (Strong), mode of inheritance: AR
familial hemophagocytic lymphohistiocytosis 3 (Strong), mode of inheritance: AR
hereditary hemophagocytic lymphohistiocytosis (Supportive), mode of inheritance: AR
familial hemophagocytic lymphohistiocytosis 3 (Definitive), mode of inheritance: AR
familial hemophagocytic lymphohistiocytosis 3 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemophagocytic lymphohistiocytosis, familial 3	AR	Allergy/Immunology/Infectious; Hematologic; Oncologic	Early recognition may allow prompt treatment, as individuals frequently have fatal outcomes unless treated by control of infectious triggers and chemoimmunotherapy, which can be beneficial; HSCT has been described	Allergy/Immunology/Infectious; Hematologic; Oncologic	14622600; 16825436; 16278825; 17993578; 20301617; 21881043; 21303357; 21755595; 21931115; 22146525; 21674762; 32374962

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UNC13D gene.

Familial_hemophagocytic_lymphohistiocytosis_3 (1523 variants)
Inborn_genetic_diseases (142 variants)
not_provided (116 variants)
not_specified (89 variants)
Autoinflammatory_syndrome (75 variants)
UNC13D-related_disorder (45 variants)
Familial_hemophagocytic_lymphohistiocytosis (18 variants)
See_cases (5 variants)
Intellectual_disability (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UNC13D gene is commonly pathogenic or not. These statistics are base on transcript: NM_000199242.3. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	421 clinvar	3 clinvar	431
missense	3 clinvar	11 clinvar	506 clinvar	27 clinvar	3 clinvar	550
nonsense	35 clinvar	14 clinvar	1 clinvar			50
start loss						0
frameshift	57 clinvar	14 clinvar	2 clinvar			73
splice donor/acceptor (+/-2bp)	10 clinvar	34 clinvar	1 clinvar			45
Total	105	73	517	448	6

Highest pathogenic variant AF is 0.00035217556

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UNC13D	protein_coding	protein_coding	ENST00000207549	32	17493

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.09e-18	0.998	125591	0	157	125748	0.000624

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.241	662	645	1.03	0.0000434	6963
Missense in Polyphen		213	201.87	1.0551		2318
Synonymous	0.503	273	284	0.962	0.0000196	2212
Loss of Function	3.09	40	67.3	0.594	0.00000357	693

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000627	0.000626
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000437	0.000435
Finnish	0.000236	0.000185
European (Non-Finnish)	0.00102	0.000950
Middle Eastern	0.000437	0.000435
South Asian	0.000458	0.000457
Other	0.000491	0.000489

dbNSFP

Source: dbNSFP

Function: FUNCTION: Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse. Regulates assembly of recycling and late endosomal structures, leading to the formation of an endosomal exocytic compartment that fuses with perforin-containing granules at the immunologic synapse and licences them for exocytosis. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells. {ECO:0000269|PubMed:15548590, ECO:0000269|PubMed:17237785}.;
Disease: DISEASE: Familial hemophagocytic lymphohistiocytosis 3 (FHL3) [MIM:608898]: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. {ECO:0000269|PubMed:14622600}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Deregulation of Rab and Rab Effector Genes in Bladder Cancer;Neutrophil degranulation;Innate Immune System;Immune System (Consensus)

Recessive Scores

pRec: 0.160

Intolerance Scores

loftool: 0.763
rvis_EVS: 0.08
rvis_percentile_EVS: 59.44

Haploinsufficiency Scores

pHI: 0.102
hipred: N
hipred_score: 0.492
ghis: 0.611

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.823

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Unc13d
Phenotype: homeostasis/metabolism phenotype; hematopoietic system phenotype; immune system phenotype; skeleton 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);

Gene ontology

Biological process: granuloma formation;germinal center formation;phagocytosis;regulation of mast cell degranulation;neutrophil degranulation;natural killer cell degranulation;positive regulation of exocytosis;defense response to virus;positive regulation of substrate adhesion-dependent cell spreading;positive regulation of regulated secretory pathway
Cellular component: extracellular region;lysosome;late endosome;cytosol;membrane;Weibel-Palade body;azurophil granule lumen;intracellular membrane-bounded organelle;recycling endosome;exocytic vesicle
Molecular function: protein binding;Rab GTPase binding