SH2D1A

SH2 domain containing 1A, the group of SH2 domain containing

Basic information

Region (hg38): X:124227867-124373197

Previous symbols: [ "IMD5", "LYP" ]

Links

ENSG00000183918 ∙ NCBI:4068 ∙ OMIM:300490 ∙ HGNC:10820 ∙ Uniprot:O60880 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked lymphoproliferative disease due to SH2D1A deficiency (Supportive), mode of inheritance: XL
• X-linked lymphoproliferative disease due to SH2D1A deficiency (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lymphoproliferative syndrome, X-linked, 1	XL	Allergy/Immunology/Infectious; Hematologic; Oncologic	Surveillance for EBV infections is indicated; Prompt recognition and treatment of hemophagocytic lymphohistiocytosis (with immunologic agents or rituximab in the case of EBV infection); Treatment for individuals with hypogammaglobulinemia (with IVIG) may be beneficial; Awareness of the increased risk of lymphoma may allow prompt recognition and treatment; HSCT has been described, and is indicated in many individuals	Allergy/Immunology/Infectious; Hematologic; Oncologic	4852784; 48119; 7188959; 6283885; 1847089; 8559596; 9771704; 11133747; 17620557; 20926771; 21971331; 32374962

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SH2D1A gene.

• X-linked lymphoproliferative disease due to SH2D1A deficiency (87 variants)
• not provided (34 variants)
• Autoinflammatory syndrome (6 variants)
• not specified (4 variants)
• Lymphoproliferative disorder (2 variants)
• X-linked lymphoproliferative syndrome (2 variants)
• Inborn genetic diseases (2 variants)
• Mullegama-Klein-Martinez syndrome;Holoprosencephaly 13, X-linked (1 variants)
• SH2D1A-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SH2D1A 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			2	11	1	14
missense	3	1	18	1		23
nonsense	6					6
start loss	1	1				2
frameshift	2	1				3
inframe indel			1			1
splice donor/acceptor (+/-2bp)	3	2				5
splice region		2	3	4		9
non coding			12	8	19	39
Total	15	5	33	20	20

Variants in SH2D1A

This is a list of pathogenic ClinVar variants found in the SH2D1A region.

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

Position	Type	Phenotype	Significance	ClinVar
X-124333698-C-A			Likely benign (Jan 01, 2023)
X-124333893-G-A			Likely benign (Dec 01, 2022)
X-124334064-A-T			Likely benign (Apr 01, 2023)
X-124335002-G-A			Likely benign (Nov 01, 2022)
X-124346012-G-A			Benign (Jan 10, 2019)
X-124346149-G-A			Benign (Jan 10, 2019)
X-124346297-C-T		X-linked lymphoproliferative disease due to SH2D1A deficiency • Autoinflammatory syndrome	Benign (Jan 14, 2022)
X-124346325-G-C		X-linked lymphoproliferative disease due to SH2D1A deficiency	Benign/Likely benign (Apr 03, 2019)
X-124346396-G-A		X-linked lymphoproliferative disease due to SH2D1A deficiency	Benign (Jan 13, 2018)
X-124346519-T-A		X-linked lymphoproliferative disease due to SH2D1A deficiency	Conflicting classifications of pathogenicity (Jan 01, 2023)
X-124346569-T-A		X-linked lymphoproliferative disease due to SH2D1A deficiency	Benign/Likely benign (Jul 07, 2023)
X-124346633-C-T		X-linked lymphoproliferative disease due to SH2D1A deficiency	Pathogenic (Oct 01, 1998)
X-124346643-A-G		X-linked lymphoproliferative disease due to SH2D1A deficiency	Pathogenic (Jan 03, 2023)
X-124346644-T-C		X-linked lymphoproliferative disease due to SH2D1A deficiency • Autoinflammatory syndrome	Pathogenic/Likely pathogenic (Aug 10, 2022)
X-124346645-G-T		X-linked lymphoproliferative disease due to SH2D1A deficiency	Pathogenic (Aug 07, 2000)
X-124346647-A-G		X-linked lymphoproliferative disease due to SH2D1A deficiency	Likely pathogenic (Sep 07, 2018)
X-124346649-G-T		X-linked lymphoproliferative disease due to SH2D1A deficiency • Autoinflammatory syndrome • not specified	Conflicting classifications of pathogenicity (Dec 13, 2023)
X-124346662-A-G		X-linked lymphoproliferative syndrome	Pathogenic (Apr 13, 2018)
X-124346665-A-C		X-linked lymphoproliferative disease due to SH2D1A deficiency	Conflicting classifications of pathogenicity (Nov 28, 2023)
X-124346687-C-T		X-linked lymphoproliferative disease due to SH2D1A deficiency	Likely benign (Sep 10, 2023)
X-124346690-C-A		not specified • X-linked lymphoproliferative disease due to SH2D1A deficiency	Benign/Likely benign (Dec 19, 2023)
X-124346690-C-T		not specified • X-linked lymphoproliferative disease due to SH2D1A deficiency • Mullegama-Klein-Martinez syndrome;Holoprosencephaly 13, X-linked	Benign/Likely benign (Jan 29, 2024)
X-124346695-A-G		X-linked lymphoproliferative disease due to SH2D1A deficiency	Conflicting classifications of pathogenicity (Jul 08, 2023)
X-124346704-T-G			Uncertain significance (Aug 01, 2020)
X-124346721-G-GGCAGCTATTTGCTGAGGGACA		X-linked lymphoproliferative disease due to SH2D1A deficiency	Uncertain significance (Nov 23, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SH2D1A	protein_coding	protein_coding	ENST00000371139	4	26812

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.389	0.572	125214	0	1	125215	0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.69	17	50.9	0.334	0.00000395	816
Missense in Polyphen		6	25.673	0.23371		391
Synonymous	0.260	19	20.5	0.927	0.00000178	253
Loss of Function	1.64	1	4.93	0.203	3.84e-7	84

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000365	0.0000365
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with SH2D1B/EAT-2. Initially it has been proposed that association with SLAMF1 prevents SLAMF1 binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1 (PubMed:12458214). Positively regulates CD244/2B4- and CD84- mediated natural killer (NK) cell functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated NK cell activation. In the context of NK cell-mediated cytotoxicity enhances conjugate formation with target cells (By similarity). May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3. {ECO:0000250|UniProtKB:O88890, ECO:0000269|PubMed:11806999, ECO:0000269|PubMed:12458214, ECO:0000305|PubMed:21219180}.
• Pathway: Natural killer cell mediated cytotoxicity - Homo sapiens (human);Measles - Homo sapiens (human);Integrated Lung Cancer Pathway;Immune System;Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell;Adaptive Immune System;Direct p53 effectors (Consensus)

Recessive Scores

• pRec: 0.453

Intolerance Scores

• loftool: 0.413
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58

Haploinsufficiency Scores

• pHI: 0.504
• hipred: Y
• hipred_score: 0.696
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low

Mouse Genome Informatics

• Gene name: Sh2d1a
• Phenotype: homeostasis/metabolism phenotype; immune system phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: adaptive immune response;humoral immune response;cellular defense response;cell-cell signaling;positive regulation of signal transduction;innate immune response;positive regulation of natural killer cell mediated cytotoxicity;regulation of immune response
• Cellular component: cytoplasm;cytosol
• Molecular function: SH3/SH2 adaptor activity;protein binding