SH3BP2

protein-coding

SH3 domain binding protein 2, the group of Pleckstrin homology domain containing|SH2 domain containing

Gene summary

The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

MANE transcript

NM_001122681.2

Inheritance

ClinVar variants

P:11U:369B:222

Top phenotype

Cherubism

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr4:2,793,023-2,841,291

External References & Databases

Ensembl (ENSG00000087266)

Transcript & Mutation Effects

hg38 • Region Span ~48.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cherubismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007315

Submitter: G2P

cherubismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007315

Submitter: PanelApp Australia

cherubismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007315

Submitter: Orphanet

cherubismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007315

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

CherubismAD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As bone lesions are typically self-limiting, surgical interventions treatment may not be necessary (with the exception of aggressive lesions resulting in severe functional issues, or for aesthetic reasons)

Refs: 11381256; 17368082; 18596838; 19017279; 20301316; 21045962; 22153076; 22640988; 22640403; 22795151

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH3BP2 variants in ClinVar

8 Conditions Cataloged

Fibrous dysplasia of jawTotal: 692

Inborn genetic diseasesTotal: 141

not specifiedTotal: 108

not providedTotal: 51

SH3BP2-related disorderTotal: 33

Congenital heart diseaseTotal: 1

Intellectual disabilityTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001122681.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	166 clinvar	3 clinvar	173
missense	5 clinvar	6 clinvar	332 clinvar	50 clinvar	1 clinvar	394
nonsense			6 clinvar	1 clinvar		7
start loss			1 clinvar			1
frameshift			18 clinvar			18
splice donor/acceptor (+/-2bp)			8 clinvar	1 clinvar		9
Total	5	6	369	218	4	602

Highest pathogenic variant AF is 0.0000014009802

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 99 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001122681.2	RefSeq	NP_001116153.1	12	MANE Select
ENST00000503393.8	Ensembl	ENSP00000422168.3	12	MANE Select
NM_001145855.2	RefSeq	NP_001139327.1	13	Standard
NM_001145856.2	RefSeq	NP_001139328.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Natural killer cell mediated cytotoxicity - Homo sapiens (human)
B Cell Receptor Signaling Pathway
TCR
BCR
TCR signaling in na&#xef

Biological Process

signal transduction
positive regulation of signal transduction

Molecular Function

phosphotyrosine residue binding
SH3/SH2 adaptor activity
protein binding
SH3 domain binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000503393
Coding exons: 13
Length: 48076
Individuals with no LoFs: 125638
Homozygous LoFs: 0
Heterozygous LoFs: 110
Defined: 125748
p: 0.000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.292	344	360	0.957	0.0000236	3972
Missense (PolyPhen)		97	105.97	0.91532		1087
Synonymous	-1.45	179	156	1.15	0.0000115	1287
Loss of Function	1.02	20	25.6	0.781	0.00000136	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00022	0.00022	rare
Finnish	0.0016	0.00074	notable
European (Non-Finnish)	0.00066	0.00062	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds differentially to the SH3 domains of certain proteins of signal transduction pathways. Binds to phosphatidylinositols; linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation dependent mechanism.;
Disease: DISEASE: Cherubism (CRBM) [MIM:118400]: An autosomal dominant syndrome characterized by excessive bone degradation of the upper and lower jaws, which often begins around three years of age. It is followed by development of fibrous tissue masses, which causes a characteristic facial swelling. {ECO:0000269|PubMed:11381256, ECO:0000269|PubMed:12900899, ECO:0000269|PubMed:14577811}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.0376
RVIS EVS: -0.84
RVIS percentile EVS: 11.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.760

Gene Damage Prediction

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