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

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoinflammation with episodic fever and immune dysregulation	AR	Allergy/Immunology/Infectious	The condition involves autoinflammation, with signs of immunodeficiency, and medical management (eg, with TNF inhibitors, IVIG, and corticosteroids) has been described as beneficial	Allergy/Immunology/Infectious	38609546

ClinVar

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

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.

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				1	1	2
missense			30	2	3	35
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding					2	2
Total	0	0	30	3	6

Variants in SHARPIN

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

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

Position	Type	Phenotype	Significance	ClinVar
8-144098905-C-G		not specified	Uncertain significance (Jun 17, 2024)
8-144098924-G-A		not specified	Uncertain significance (Mar 31, 2024)
8-144098945-G-C		not specified	Uncertain significance (May 24, 2023)
8-144098948-C-T			Benign (Apr 02, 2018)
8-144098981-C-T		not specified	Uncertain significance (Feb 15, 2023)
8-144099086-G-A		not specified	Uncertain significance (Dec 19, 2022)
8-144099167-C-T		not specified	Uncertain significance (Nov 21, 2023)
8-144099183-G-C		not specified	Uncertain significance (Dec 04, 2023)
8-144099283-C-A		not specified	Uncertain significance (Nov 17, 2022)
8-144099315-G-C		not specified	Uncertain significance (Apr 01, 2024)
8-144099319-G-A		not specified	Benign (Mar 29, 2016)
8-144099357-C-T		not specified	Uncertain significance (Aug 16, 2022)
8-144099393-C-T		not specified	Uncertain significance (Dec 14, 2022)
8-144099394-G-A		not specified	Uncertain significance (Apr 12, 2024)
8-144099535-C-T		not specified	Uncertain significance (Nov 15, 2021)
8-144099544-T-C		not specified	Uncertain significance (Mar 24, 2023)
8-144099585-G-A		not specified	Likely benign (Dec 11, 2023)
8-144099719-G-A		not specified	Uncertain significance (Aug 04, 2021)
8-144099724-C-G		not specified	Uncertain significance (Jul 21, 2022)
8-144099747-CAG-C		Autoinflammation with episodic fever and immune dysregulation	Pathogenic (Apr 25, 2024)
8-144099755-C-T		not specified	Uncertain significance (Oct 26, 2022)
8-144099785-G-C		not specified	Uncertain significance (Apr 13, 2023)
8-144099794-C-G		not specified	Uncertain significance (Mar 14, 2023)
8-144099812-C-G		not specified	Uncertain significance (Jan 23, 2024)
8-144099812-C-T		not specified	Uncertain significance (Feb 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SHARPIN	protein_coding	protein_coding	ENST00000398712	8	9492

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000231	0.919	124780	0	16	124796	0.0000641

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0439	215	213	1.01	0.0000118	2361
Missense in Polyphen		53	61.239	0.86546		701
Synonymous	-1.92	116	92.5	1.25	0.00000549	871
Loss of Function	1.63	10	17.3	0.577	8.17e-7	184

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000131	0.000131
Ashkenazi Jewish	0.0000998	0.0000993
East Asian	0.000111	0.000111
Finnish	0.00	0.00
European (Non-Finnish)	0.0000626	0.0000618
Middle Eastern	0.000111	0.000111
South Asian	0.000104	0.0000980
Other	0.00	0.00

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

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

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