SH3KBP1

protein-coding

SH3 domain containing kinase binding protein 1

Gene summary

This gene encodes an adapter protein that contains one or more N-terminal Src homology domains, a proline rich region and a C-terminal coiled-coil domain. The encoded protein facilitates protein-protein interactions and has been implicated in numerous cellular processes including apoptosis, cytoskeletal rearrangement, cell adhesion and in the regulation of clathrin-dependent endocytosis. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

MANE transcript

NM_031892.3

Inheritance

ClinVar variants

U:313B:142

Top phenotype

Immunodeficiency 61

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:19,533,977-19,887,600

External References & Databases

Ensembl (ENSG00000147010)

Transcript & Mutation Effects

hg38 • Region Span ~353.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 61LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010296

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 61LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010296

Submitter: ClinGen

SH3KBP1 (SH3-Domain Kinase-Binding Protein 1) was first reported in relation to X-linked Recessive Immunodeficiency 61 in 2018 by Keller et al (PMID: 29636373). Immunodeficiency 61 is a primary immunodeficiency characterized by the onset of recurrent bacterial infections in early childhood due to impaired antibody production. Affected individuals have normal numbers of circulating B and T cells, but B cells have an intrinsic defect in antibody production. At least 1 unique variant (an intragenic deletion encompassing exon 2 to exon 6) has been reported in humans (PMID: 29636373). Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data (1.5 points): Variants in this gene have been reported in 2 siblings in 1 publication (PMID: 29636373). Phenotypes described in the siblings include hypogammaglobulinemia (decreased IgG2, IgG4 and IgM in sibling 1 and almost complete absence of all Ig isotypes in sibling 2) and recurrent bacterial infections (in early childhood in sibling 1 and until death at age 15 years in sibling 2). Summary of experimental data (4 points): SH3KBP1-knockout mice were found to recapitulate the cellular and molecular phenotype seen in the human patient with impaired response to immunization (PMID: 21708930). Additionally, interaction with BLNK (PMID: 11071869) indicate a potential role of CIN85 in the B cell receptor-mediated signaling pathway, which was altered in SH3KBP1 deficient cells both from patients and non-patient sources (PMID: 29636373). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

immunodeficiency 61LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010296

Submitter: Ambry Genetics

immunodeficiency 61MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010296

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 61XL

Manifestation: Allergy/Immunology/Infectious; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: The condition has been described as including early-onset, severe infections, and awareness may allow preventative measures and early and aggressive treatment of infections

Refs: 29636373

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH3KBP1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 348

not specifiedTotal: 99

SH3KBP1-related disorderTotal: 13

Laterality defects, autosomal dominantTotal: 1

Immunodeficiency 61Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031892.3. 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			29 clinvar	122 clinvar	4 clinvar	155
missense			220 clinvar	15 clinvar	1 clinvar	236
nonsense			17 clinvar			17
start loss			1 clinvar			1
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			44 clinvar			44
Total	0	0	313	137	5	455

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031892.3	RefSeq	NP_114098.1	18	MANE Select
ENST00000397821.8	Ensembl	ENSP00000380921.3	18	MANE Select
NM_001024666.3	RefSeq	NP_001019837.1	17	Standard
NM_001184960.2	RefSeq	NP_001171889.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sh3kbp1	Danio rerio	Structure: blood cell Quality: accumulation abnormal

Gene / Model

Organism

Observed Phenotype

sh3kbp1

Danio rerio

Structure: blood cell

Quality: accumulation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
EGF-EGFR Signaling Pathway
Developmental Biology
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
Disease

Biological Process

endocytosis
apoptotic process
cytoskeleton organization
cell-cell signaling
axon guidance

Molecular Function

protein binding
SH3 domain binding

Cellular Component

cytoplasm
cytosol
cytoskeleton
plasma membrane
cell-cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397821
Coding exons: 18
Length: 353627
Individuals with no LoFs: 125323
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125324
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.05	178	273	0.651	0.0000225	4329
Missense (PolyPhen)		19	47.477	0.40019		759
Synonymous	-1.25	138	121	1.14	0.0000114	1305
Loss of Function	4.39	1	24.4	0.0410	0.00000178	454

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein involved in regulating diverse signal transduction pathways. Involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through an association with CBL and endophilins. The association with CBL, and thus the receptor internalization, may inhibited by an interaction with PDCD6IP and/or SPRY2. Involved in regulation of ligand-dependent endocytosis of the IgE receptor. Attenuates phosphatidylinositol 3-kinase activity by interaction with its regulatory subunit (By similarity). May be involved in regulation of cell adhesion; promotes the interaction between TTK2B and PDCD6IP. May be involved in the regulation of cellular stress response via the MAPK pathways through its interaction with MAP3K4. Is involved in modulation of tumor necrosis factor mediated apoptosis. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. {ECO:0000250, ECO:0000269|PubMed:11894095, ECO:0000269|PubMed:11894096, ECO:0000269|PubMed:12177062, ECO:0000269|PubMed:12734385, ECO:0000269|PubMed:12771190, ECO:0000269|PubMed:15090612, ECO:0000269|PubMed:15707590, ECO:0000269|PubMed:16177060, ECO:0000269|PubMed:16256071, ECO:0000269|PubMed:21834987}.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.309
RVIS EVS: -0.42
RVIS percentile EVS: 25.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.704

Gene Damage Prediction

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