GeneBe

SHARPIN

SHANK associated RH domain interactor, the group of Linear ubiquitin chain assembly complex |Zinc fingers RANBP2-type

Basic information

Region (hg38): 8:144098633-144108124

Links

ENSG00000179526 ∙ NCBI:81858 ∙ OMIM:611885 ∙ HGNC:25321 ∙ Uniprot:Q9H0F6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • autoinflammation with episodic fever and immune dysregulation (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Autoinflammation with episodic fever and immune dysregulationARAllergy/Immunology/InfectiousThe condition involves autoinflammation, with signs of immunodeficiency, and medical management (eg, with TNF inhibitors, IVIG, and corticosteroids) has been described as beneficialAllergy/Immunology/Infectious38609546

ClinVar

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

  • not_specified (65 variants)
  • not_provided (3 variants)
  • Autoinflammation_with_episodic_fever_and_immune_dysregulation (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SHARPIN gene is commonly pathogenic or not. These statistics are base on transcript: NM_000030974.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
 1
missense
60
clinvar
5
clinvar
 65
nonsense
0
start loss
0
frameshift
2
clinvar
 2
splice donor/acceptor (+/-2bp)
0
Total 2 0 60 6 0

Highest pathogenic variant AF is 6.8437555e-7

Loading clinvar variants...

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SHARPINprotein_codingprotein_codingENST00000398712 89492
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.00002310.9191247800161247960.0000641
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.04392152131.010.00001182361
Missense in Polyphen5361.2390.86546701
Synonymous-1.9211692.51.250.00000549871
Loss of Function1.631017.30.5778.17e-7184

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001310.000131
Ashkenazi Jewish0.00009980.0000993
East Asian0.0001110.000111
Finnish0.000.00
European (Non-Finnish)0.00006260.0000618
Middle Eastern0.0001110.000111
South Asian0.0001040.0000980
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF- RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. {ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181}.;
Pathway
Necroptosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Signal Transduction;Neuronal System;TNFR1-induced NFkappaB signaling pathway;TNF signaling;Death Receptor Signalling;Regulation of TNFR1 signaling;Neurexins and neuroligins;Protein-protein interactions at synapses (Consensus)

Recessive Scores

pRec
0.0834

Intolerance Scores

loftool
0.359
rvis_EVS
0.11
rvis_percentile_EVS
61.91

Haploinsufficiency Scores

pHI
0.0677
hipred
N
hipred_score
0.432
ghis
0.390

Essentials

essential_gene_CRISPR
E
essential_gene_CRISPR2
S
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.922

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Sharpin
Phenotype
digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; skeleton phenotype; respiratory system phenotype; liver/biliary system phenotype; reproductive system phenotype; 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); craniofacial 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;

Gene ontology

Biological process
mitochondrion organization;I-kappaB kinase/NF-kappaB signaling;brain development;regulation of tumor necrosis factor-mediated signaling pathway;apoptotic nuclear changes;keratinization;positive regulation of I-kappaB kinase/NF-kappaB signaling;proteasome-mediated ubiquitin-dependent protein catabolic process;negative regulation of inflammatory response;protein homooligomerization;protein linear polyubiquitination;regulation of CD40 signaling pathway
Cellular component
cytosol;postsynaptic density;cell junction;dendrite;LUBAC complex
Molecular function
ubiquitin-protein transferase activity;protein binding;polyubiquitin modification-dependent protein binding;identical protein binding;ubiquitin binding;protein-containing complex binding;metal ion binding