SASH3

protein-coding

SAM and SH3 domain containing 3, the group of SAM and SH3 domain containing|Sterile alpha motif domain containing

Gene summary

The protein encoded by this gene contains a Src homology-3 (SH3) domain and a sterile alpha motif (SAM), both of which are found in proteins involved in cell signaling. This protein may function as a signaling adapter protein in lymphocytes.[provided by RefSeq, Sep 2009]

Previous symbols:

CXorf9

MANE transcript

NM_018990.4

Inheritance

ClinVar variants

P:5U:78B:7

Top phenotype

Immunodeficiency 102

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chrX:129,779,949-129,795,201

External References & Databases

Ensembl (ENSG00000122122)

Transcript & Mutation Effects

hg38 • Region Span ~15.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 102STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024781

Submitter: PanelApp Australia

immunodeficiency 102DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0024781

Submitter: Ambry Genetics

immunodeficiency 102STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024781

Submitter: Labcorp Genetics (formerly Invitae)

combined immunodeficiency, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010730

Submitter: ClinGen

SAM- and SH3 domain-containing protein 3; *SASH3*, also known as SH3 containing Lymphocyte Protein (*SLY1*) encodes an adaptor scaffolding protein that is vital for integration and propagation of signal transduction cascades in lymphocytes. SASH3 protein is phosphorylated at Ser27 following T- or B-cell receptor ligation and protein kinase C (PKC) activation. The phenotype associated with combined immunodeficiency due to *SASH3* variants is characterized by recurrent infections and multilineage immunodeficiency. *SASH3* was first reported in relation to combined immunodeficiency X- linked in 2021 (Delmonte et al., PMID: 33876203). The study reported four unrelated male patients carrying three hemizygous LOF variants in the *SASH3* gene. Patients manifested in early childhood with recurrent sinopulmonary, cutaneous, and mucosal infections, and refractory autoimmune cytopenias. Horrillo et al., 2022 reported a man with a milder form of combined immunodeficiency and a novel truncating *SASH3* variant which led to a complete absence of the protein (PMID: 35464398). The reported patients exhibited CD4+ T-cell lymphopenia, defective T cell activation and proliferation, and B cell lymphopenia. Mother heterozygosity was confirmed in three of the five patients reported. This gene-disease relationship is also supported by rescue, animal model and expression evidence. Correction of the proliferative defect of SASH3−/− Jurkat cells occurred upon transduction with the SASH3 LV vector. Transduction efficiency was also evident by reconstitution of PLCγ1 phosphorylation in SASH3-transduced Patient T cells upon in vitro stimulation with anti-CD3 and anti-CD28 (PMID: 33876203). Two different Sly1 deficient mice models recapitulated the human phenotype (PMIDs: 16227612 and 19604361). Both Sly1Δ/Δ and Sly1-/- showed that absence of SLY1 protein affects CD4 T cell development, T-cell proliferation, and cytokine production and impairs antibody response to T- dependent and T- independent antigens. Preferential SASH3 expression in lymph nodes and thymus gland indicates an essential role in the development and activation of lymphocytes (PMIDs: 24309898 and 25970244). In summary, *SASH3* is definitively associated with combined immunodeficiency X-linked. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time.

Clinical Genomic Database (CGD)

Immunodeficiency 102XL

Manifestation: Allergy/Immunology/Infectious; Hematologic

Intervention: Allergy/Immunology/Infectious

Rationale: The condition can involve immunodeficiencies as well as immune dysregulation, and prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 33876203; 35464398

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SASH3 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 46

not providedTotal: 10

Immunodeficiency 102Total: 6

SASH3-related conditionTotal: 2

ImmunodeficiencyTotal: 1

Primary immunodeficiency or monogenic inflammatory bowel diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018990.4. 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			6 clinvar	2 clinvar		8
missense	1 clinvar		66 clinvar	5 clinvar		72
nonsense	3 clinvar	1 clinvar	1 clinvar			5
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	4	1	78	7	0	90

Highest pathogenic variant AF is 0.0000036437373

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018990.4	RefSeq	NP_061863.1	8	MANE Select
ENST00000356892.4	Ensembl	ENSP00000349359.3	8	MANE Select
ENST00001044905.1	Ensembl	ENSP00000714722.1	7	Standard
ENST00001044906.1	Ensembl	ENSP00000714723.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of immunoglobulin production
positive regulation of T cell cytokine production
positive regulation of adaptive immune response
positive regulation of B cell proliferation
positive regulation of interferon-gamma production

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356892
Coding exons: 8
Length: 15223
Individuals with no LoFs: 125715
Homozygous LoFs: 1
Heterozygous LoFs: 2
Defined: 125718
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.85	98	165	0.595	0.0000138	2483
Missense (PolyPhen)		17	59.636	0.28506		917
Synonymous	-1.30	88	73.8	1.19	0.00000660	773
Loss of Function	2.65	3	13.5	0.222	0.00000124	192

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00015	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000063	0.000046	rare
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a signaling adapter protein in lymphocytes. {ECO:0000250}.;

Recessive Scores

pRec: 0.263

Intolerance Scores

LoFtool: 0.0772
RVIS EVS: -0.45
RVIS percentile EVS: 24.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.227

Gene Damage Prediction

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