HMGB1

high mobility group box 1, the group of Canonical high mobility group

Basic information

Region (hg38): 13:30456703-30617597

Previous symbols: [ "HMG1" ]

Links

ENSG00000189403 ∙ NCBI:3146 ∙ OMIM:163905 ∙ HGNC:4983 ∙ Uniprot:P09429 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HMGB1 gene.

• not provided (8 variants)
• Inborn genetic diseases (2 variants)
• HMGB1-related Developmental delay and microcephaly (1 variants)
• HMGB1-associated disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGB1 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		2
missense			1	1		2
nonsense						0
start loss						0
frameshift		2	1			3
inframe indel			1		1	2
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding					3	3
Total	0	2	3	3	4

Variants in HMGB1

This is a list of pathogenic ClinVar variants found in the HMGB1 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-30459095-C-T			Benign (Jan 10, 2019)
13-30459175-C-CTTAA			Benign (Apr 28, 2020)
13-30461384-ATCT-A		Inborn genetic diseases	Uncertain significance (Mar 28, 2022)
13-30461402-TTCC-T			Benign (May 01, 2023)
13-30461417-A-C		Inborn genetic diseases	Uncertain significance (Jan 30, 2024)
13-30461422-CTT-C		HMGB1-related Developmental delay and microcephaly	Uncertain significance (Feb 02, 2022)
13-30461426-A-G			Likely benign (Sep 01, 2022)
13-30461445-TCTTC-T		Brachyphalangy, polydactyly, and tibial aplasia/hypoplasia	Pathogenic (Jun 01, 2022)
13-30461450-CTTCT-C		Brachyphalangy, polydactyly, and tibial aplasia/hypoplasia	Pathogenic (Jun 01, 2022)
13-30461464-T-C			Likely benign (Dec 31, 2019)
13-30461496-G-A		Inborn genetic diseases	Uncertain significance (Aug 16, 2021)
13-30462544-A-A			Benign (Dec 31, 2019)
13-30462601-AGT-A			Likely pathogenic (Sep 15, 2021)
13-30462700-G-A		HMGB1-related disorder	Benign (Nov 14, 2019)
13-30463266-G-A			Likely benign (Mar 29, 2018)
13-30463308-T-C		HMGB1-related disorder	Benign (Oct 28, 2019)
13-30463632-CAT-C		HMGB1-associated disorder	Likely pathogenic (Nov 27, 2023)
13-30463655-G-A		Inborn genetic diseases	Uncertain significance (Mar 06, 2024)
13-30463675-G-C		HMGB1-related disorder	Likely benign (May 10, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGB1	protein_coding	protein_coding	ENST00000405805	4	158851

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.820	0.179	105181	0	2	105183	0.00000951

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.69	30	109	0.275	0.00000542	1439
Missense in Polyphen		0	10.533	0		193
Synonymous	-0.622	42	37.2	1.13	0.00000196	339
Loss of Function	2.64	1	10.0	0.0997	5.44e-7	150

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)	0.0000204	0.0000204
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability. Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury (PubMed:27362237). Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogdenic activity (By similarity). May be involved in platelet activation (By similarity). Binds to phosphatidylserine and phosphatidylethanolamide (By similarity). Bound to RAGE mediates signaling for neuronal outgrowth (By similarity). May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP (PubMed:23303669, PubMed:25549101). {ECO:0000250|UniProtKB:P10103, ECO:0000250|UniProtKB:P12682, ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:23303669, ECO:0000269|PubMed:25549101, ECO:0000269|PubMed:27362237, ECO:0000305|PubMed:23446148, ECO:0000305|PubMed:23519706, ECO:0000305|PubMed:23994764, ECO:0000305|PubMed:25048472}.; FUNCTION: In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation (PubMed:20819940). Involved in oxidative stress-mediated autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury (By similarity). In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy (By similarity). Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages (By similarity). {ECO:0000250|UniProtKB:P63158, ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:21395369}.
• Pathway: Autophagy - animal - Homo sapiens (human);Base excision repair - Homo sapiens (human);Necroptosis - Homo sapiens (human);Retinoblastoma (RB) in Cancer;DNA Damage Response (only ATM dependent);Toll Like Receptor 7/8 (TLR7/8) Cascade;Neutrophil degranulation;Signaling by Interleukins;the information processing pathway at the ifn beta enhancer;apoptotic dna-fragmentation and tissue homeostasis;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;DEx/H-box helicases activate type I IFN and inflammatory cytokines production ;Interleukin-1 signaling;Innate Immune System;Immune System;Activation of DNA fragmentation factor;Apoptosis induced DNA fragmentation;Apoptotic execution phase;Apoptosis;Programmed Cell Death;RIP-mediated NFkB activation via ZBP1;Beta3 integrin cell surface interactions;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;MyD88 dependent cascade initiated on endosome;Regulation of TLR by endogenous ligand;Advanced glycosylation endproduct receptor signaling;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Endogenous TLR signaling;amb2 Integrin signaling;Interleukin-1 family signaling (Consensus)

Intolerance Scores

• loftool: 0.153
• rvis_EVS: -0.21
• rvis_percentile_EVS: 38.28

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.752
• ghis: 0.692

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0226

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hmgb1
• Phenotype: vision/eye phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; hematopoietic 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); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: hmgb1a
• Affected structure: dopaminergic neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;eye development;myeloid dendritic cell activation;endothelial cell proliferation;activation of innate immune response;toll-like receptor signaling pathway;plasmacytoid dendritic cell activation;macrophage activation involved in immune response;dendritic cell chemotaxis;inflammatory response to antigenic stimulus;regulation of tolerance induction;regulation of T cell mediated immune response to tumor cell;DNA topological change;base-excision repair;apoptotic DNA fragmentation;DNA recombination;chromatin remodeling;chromatin silencing;regulation of transcription by RNA polymerase II;autophagy;inflammatory response;positive regulation of cytosolic calcium ion concentration;regulation of signaling receptor activity;regulation of autophagy;positive regulation of autophagy;negative regulation of RNA polymerase II transcriptional preinitiation complex assembly;lung development;neuron projection development;chromatin assembly;regulation of restriction endodeoxyribonuclease activity;activation of protein kinase activity;DNA geometric change;positive regulation of mismatch repair;developmental process;negative regulation of interferon-gamma production;positive regulation of interferon-beta production;positive regulation of interleukin-10 production;positive regulation of interleukin-12 production;positive regulation of interleukin-6 production;positive regulation of tumor necrosis factor production;V(D)J recombination;positive regulation of toll-like receptor 2 signaling pathway;positive regulation of toll-like receptor 4 signaling pathway;positive regulation of toll-like receptor 9 signaling pathway;T-helper 1 cell activation;endothelial cell chemotaxis;positive regulation of activated T cell proliferation;positive regulation of apoptotic process;apoptotic cell clearance;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;neutrophil degranulation;negative regulation of CD4-positive, alpha-beta T cell differentiation;positive regulation of DNA binding;positive regulation of MAPK cascade;positive regulation of blood vessel endothelial cell migration;negative regulation of blood vessel endothelial cell migration;T-helper 1 cell differentiation;innate immune response;positive regulation of innate immune response;positive regulation of myeloid cell differentiation;positive regulation of glycogen catabolic process;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;positive regulation of interleukin-1 secretion;positive regulation of interleukin-1 beta secretion;positive chemotaxis;DNA ligation involved in DNA repair;positive regulation of DNA ligation;response to glucocorticoid;cell chemotaxis;positive regulation of ERK1 and ERK2 cascade;cellular response to lipopolysaccharide;positive regulation of monocyte chemotactic protein-1 production;positive regulation of monocyte chemotaxis;positive regulation of wound healing;neutrophil clearance;cellular response to interleukin-7;positive regulation of NIK/NF-kappaB signaling;positive regulation of interferon-alpha secretion;positive regulation of sprouting angiogenesis;positive regulation of vascular endothelial cell proliferation;tumor necrosis factor secretion;negative regulation of apoptotic cell clearance;positive regulation of interleukin-6 secretion;regulation of nucleotide-excision repair;positive regulation of dendritic cell differentiation
• Cellular component: nuclear chromatin;condensed chromosome;extracellular region;extracellular space;nucleus;nucleoplasm;cytoplasm;early endosome;endoplasmic reticulum-Golgi intermediate compartment;cell surface;transcriptional repressor complex;secretory granule lumen;alphav-beta3 integrin-HMGB1 complex;neuron projection;ficolin-1-rich granule lumen
• Molecular function: four-way junction DNA binding;bubble DNA binding;lipopolysaccharide binding;phosphatidylserine binding;damaged DNA binding;double-stranded DNA binding;single-stranded DNA binding;transcription coactivator activity;RNA binding;double-stranded RNA binding;single-stranded RNA binding;cytokine activity;integrin binding;protein binding;transcription factor binding;DNA binding, bending;calcium-dependent protein kinase regulator activity;lyase activity;C-X-C chemokine binding;protein kinase activator activity;chemoattractant activity;transcription regulatory region DNA binding;RAGE receptor binding;DNA polymerase binding;repressing transcription factor binding;supercoiled DNA binding