HCST

protein-coding

hematopoietic cell signal transducer

Gene summary

This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the immune recognition receptor complex with the C-type lectin-like receptor NKG2D. As part of this receptor complex, this protein may activate phosphatidylinositol 3-kinase dependent signaling pathways through its intracytoplasmic YxxM motif. This receptor complex may have a role in cell survival and proliferation by activation of NK and T cell responses. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Previous symbols:

PIK3AP

MANE transcript

NM_014266.4

Inheritance

—

ClinVar variants

U:14

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr19:35,902,529-35,904,377

External References & Databases

Ensembl (ENSG00000126264)

Transcript & Mutation Effects

hg38 • Region Span ~1.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HCST variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014266.4. 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			2 clinvar			2
missense			11 clinvar			11
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	14	0	0	14

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014266.4	RefSeq	NP_055081.1	4	MANE Select
ENST00000246551.9	Ensembl	ENSP00000246551.3	4	MANE Select
NM_001007469.2	RefSeq	NP_001007470.1	4	Standard
ENST00000437550.2	Ensembl	ENSP00000400516.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Natural killer cell mediated cytotoxicity - Homo sapiens (human)
Immune System
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
Adaptive Immune System

Biological Process

protein phosphorylation
positive regulation of phosphatidylinositol 3-kinase signaling
regulation of immune response

Molecular Function

signaling receptor binding
protein binding
phosphatidylinositol 3-kinase binding

Cellular Component

plasma membrane
cell surface
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246551
Coding exons: 4
Length: 1898
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125742
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.483	43	52.9	0.813	0.00000231	567
Missense (PolyPhen)		10	10.349	0.96624		109
Synonymous	1.03	17	23.3	0.728	0.00000103	215
Loss of Function	0.165	4	4.37	0.915	1.86e-7	53

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells. {ECO:0000269|PubMed:10426994, ECO:0000269|PubMed:10528161, ECO:0000269|PubMed:11015446, ECO:0000269|PubMed:11777960, ECO:0000269|PubMed:12740575, ECO:0000269|PubMed:12740576, ECO:0000269|PubMed:16002667, ECO:0000269|PubMed:16339517, ECO:0000269|PubMed:16582911, ECO:0000269|PubMed:18097042}.;

Recessive Scores

pRec: 0.192

Intolerance Scores

LoFtool: 0.515
RVIS EVS: 0.64
RVIS percentile EVS: 83.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.659

Gene Damage Prediction

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