SH2B3

SH2B adaptor protein 3, the group of Pleckstrin homology domain containing|SH2 domain containing

Basic information

Region (hg38): 12:111405922-111451623

Links

ENSG00000111252 ∙ NCBI:10019 ∙ OMIM:605093 ∙ HGNC:29605 ∙ Uniprot:Q9UQQ2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• primary familial polycythemia due to EPO receptor mutation (No Known Disease Relationship), mode of inheritance: Unknown
• schizophrenia (No Known Disease Relationship), mode of inheritance: Unknown
• thrombocythemia 1 (No Known Disease Relationship), mode of inheritance: Unknown
• growth retardation-mild developmental delay-chronic hepatitis syndrome (Supportive), mode of inheritance: AR

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SH2B3 gene.

• not provided (27 variants)
• Inborn genetic diseases (23 variants)
• not specified (14 variants)
• SH2B3-related condition (3 variants)
• Thrombocythemia 1 (3 variants)
• Primary familial polycythemia due to EPO receptor mutation (3 variants)
• Primary myelofibrosis;Thrombocythemia 1;Primary familial polycythemia due to EPO receptor mutation (1 variants)
• Primary myelofibrosis (1 variants)
• Hereditary cancer (1 variants)
• Thrombocythemia 1;Primary familial polycythemia due to EPO receptor mutation;Primary myelofibrosis (1 variants)
• Hereditary cancer-predisposing syndrome (1 variants)
• Familial myelofibrosis (1 variants)
• Developmental and epileptic encephalopathy, 67 (1 variants)
• Hepatoblastoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SH2B3 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	3	4
missense		1	32	3	6	42
nonsense			1			1
start loss	1					1
frameshift	1		1			2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			2	1	9	12
Total	2	1	36	5	18

Highest pathogenic variant AF is 0.00000658

Variants in SH2B3

This is a list of pathogenic ClinVar variants found in the SH2B3 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-111406282-G-A			Likely benign (-)
12-111417874-A-G			Benign (Feb 28, 2019)
12-111418146-A-G		Primary familial polycythemia due to EPO receptor mutation	Pathogenic (May 04, 2022)
12-111418234-G-A		Familial myelofibrosis	Uncertain significance (-)
12-111418248-G-T		Inborn genetic diseases	Uncertain significance (Aug 01, 2022)
12-111418257-G-A		not specified	Benign (May 04, 2022)
12-111418276-A-G		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
12-111418294-G-T		Inborn genetic diseases	Uncertain significance (Jun 29, 2022)
12-111418301-T-G		Inborn genetic diseases	Uncertain significance (Feb 06, 2023)
12-111418317-C-G		Inborn genetic diseases	Uncertain significance (Sep 26, 2022)
12-111418375-G-A		not specified	Uncertain significance (May 04, 2022)
12-111418377-G-A		SH2B3-related disorder	Likely benign (May 07, 2020)
12-111418478-C-T			Likely benign (Dec 31, 2019)
12-111418485-G-T		Inborn genetic diseases	Uncertain significance (Jun 23, 2023)
12-111418569-C-T			Uncertain significance (Dec 02, 2020)
12-111418594-C-A			Uncertain significance (Aug 01, 2021)
12-111418609-C-T		not specified • Thrombocythemia 1	Uncertain significance (Dec 14, 2022)
12-111418627-C-T		Primary familial polycythemia due to EPO receptor mutation	Uncertain significance (-)
12-111418639-C-G		not specified • SH2B3-related disorder	Benign (May 09, 2023)
12-111418685-G-A		not specified	Benign (Nov 26, 2021)
12-111418689-T-C		SH2B3-related disorder	Benign (May 09, 2023)
12-111418702-G-T			Likely benign (Mar 01, 2024)
12-111418744-TGCTGC-T		Primary myelofibrosis	Pathogenic (Aug 12, 2010)
12-111418750-G-C		Inborn genetic diseases	Uncertain significance (Nov 21, 2022)
12-111418767-G-C		Thrombocythemia 1 • Developmental and epileptic encephalopathy, 67 • Hepatoblastoma • Primary myelofibrosis	Conflicting classifications of pathogenicity (May 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SH2B3	protein_coding	protein_coding	ENST00000341259	7	45676

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000103	0.989	125720	0	27	125747	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.415	301	322	0.935	0.0000233	3559
Missense in Polyphen		122	138.12	0.88326		1508
Synonymous	1.93	120	150	0.800	0.0000116	1259
Loss of Function	2.24	10	21.1	0.473	0.00000115	226

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000243	0.000243
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.0000941	0.0000924
European (Non-Finnish)	0.000100	0.0000967
Middle Eastern	0.0000544	0.0000544
South Asian	0.000136	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase. {ECO:0000250}.
• Disease: DISEASE: Celiac disease 13 (CELIAC13) [MIM:612011]: A multifactorial, chronic disorder of the small intestine caused by intolerance to gluten. It is characterized by immune-mediated enteropathy associated with failed intestinal absorption, and malnutrition. In predisposed individuals, the ingestion of gluten- containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. {ECO:0000269|PubMed:18311140}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:17554260}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Neurotrophin signaling pathway - Homo sapiens (human);TYROBP Causal Network;T-Cell antigen Receptor (TCR) Signaling Pathway;Signal Transduction;Factors involved in megakaryocyte development and platelet production;TCR;Regulation of KIT signaling;Hemostasis;EPO signaling pathway;Signaling by SCF-KIT;Signaling by Receptor Tyrosine Kinases;Signaling events mediated by Stem cell factor receptor (c-Kit) (Consensus)

Recessive Scores

• pRec: 0.358

Haploinsufficiency Scores

• pHI: 0.782
• hipred: Y
• hipred_score: 0.552
• ghis: 0.430

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.679

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sh2b3
• Phenotype: cellular phenotype; immune system phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: transmembrane receptor protein tyrosine kinase signaling pathway;blood coagulation;positive regulation of signal transduction;cell differentiation;embryonic hemopoiesis;intracellular signal transduction
• Cellular component: cytosol;plasma membrane
• Molecular function: transmembrane receptor protein tyrosine kinase adaptor activity;protein binding