STK4

protein-coding

serine/threonine kinase 4

Gene summary

The protein encoded by this gene is a cytoplasmic kinase that is structurally similar to the yeast Ste20p kinase, which acts upstream of the stress-induced mitogen-activated protein kinase cascade. The encoded protein can phosphorylate myelin basic protein and undergoes autophosphorylation. A caspase-cleaved fragment of the encoded protein has been shown to be capable of phosphorylating histone H2B. The particular phosphorylation catalyzed by this protein has been correlated with apoptosis, and it's possible that this protein induces the chromatin condensation observed in this process. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006282.5

Inheritance

ClinVar variants

P:19U:126B:80

Top phenotype

Immunodeficiency 110 with lymphoproliferation

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr20:44,966,494-45,084,214

External References & Databases

Ensembl (ENSG00000101109)

Transcript & Mutation Effects

hg38 • Region Span ~117.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined immunodeficiency due to STK4 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013934

Submitter: ClinGen

*STK4* was first reported in relation to autosomal recessive combined immunodeficiency in 2012 (Abdollahpour H, et al., 2012, PMID: 22294732; Nehme NT, et al., 2012, PMID: 22174160). Serine/threonine kinase 4 (*STK4*), encodes mammalian Sterile 20-like kinase 1 (MST1; distinct from the gene *MST1* or macrophage stimulating 1) which is involved in cell death, following caspase-cleavage, it enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. It is a key component of the Hippo signaling pathway, which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. *STK4* deficiency is characterized by a progressive loss of naive T cells, the consequences of which include recurrent bacterial and viral infections and autoimmune manifestations. Curated evidence supporting the gene-disease relationship includes 6 probands plus 6 additional affected family members, with biallelic loss of function (nonsense and frameshift) variants, reported in 5 publications (PMIDs: 22294732, 22174160, 22952854, 26117625, 26801501). Parents and healthy siblings were heterozygous for the mutation, consistent with autosomal recessive inheritance (PMID: 22294732), with no evidence of dominant disease by haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, including its enhanced expression in hematopoietic tissues (PMID: 22174160) and its function in apoptosis (PMID: 11278283), which is consistent with increased cell death of naive and proliferating T cells leading to lymphopenia in patients. This function is altered in patient cells (PMID: 22294732), which also have altered expression of Foxo1, Il7Rα, L-selectin, and CCR7, which can cause altered T-cell homing to secondary lymphoid organs (PMID: 22174160). Models have recapitulated the T lymphopenia with profound loss of naïve T cells in both knockout and cell-specific knockout mice (PMIDs: 19073936, 19692642). More evidence is available in the literature, but the maximum score was reached. In summary, *STK4* is definitively associated with autosomal recessive combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date May 19, 2022 (SOP Version 8).

combined immunodeficiency due to STK4 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013934

Submitter: PanelApp Australia

combined immunodeficiency due to STK4 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013934

Submitter: Ambry Genetics

combined immunodeficiency due to STK4 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013934

Submitter: Labcorp Genetics (formerly Invitae)

combined immunodeficiency due to STK4 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013934

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 110 with lymphoproliferationAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: Individuals are susceptible to recurrent and severe viral, bacterial, and fungal infections (as well as sequelae such as EBV-related lymphoma), and and prophylaxis, as well as prompt and aggressive treatment of infections may be beneficial; Individuals may have cardiovascular anomalies, and surveillance (including with echocardiogram) may allow early detection and management; HSCT has been described

Refs: 22294732; 22174160

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STK4 variants in ClinVar

7 Conditions Cataloged

Combined immunodeficiency due to STK4 deficiencyTotal: 258

Inborn genetic diseasesTotal: 46

not providedTotal: 31

not specifiedTotal: 22

STK4-related disorderTotal: 9

Severe combined immunodeficiency diseaseTotal: 2

Inherited Immunodeficiency DiseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006282.5. 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			1 clinvar	70 clinvar		71
missense			120 clinvar	9 clinvar	1 clinvar	130
nonsense	9 clinvar	4 clinvar	1 clinvar			14
start loss			1 clinvar			1
frameshift	3 clinvar					3
splice donor/acceptor (+/-2bp)		3 clinvar	3 clinvar			6
Total	12	7	126	79	1	225

Highest pathogenic variant AF is 0.00000868992

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006282.5	RefSeq	NP_006273.1	11	MANE Select
ENST00000372806.8	Ensembl	ENSP00000361892.3	11	MANE Select
NM_001352385.2	RefSeq	NP_001339314.1	11	Standard
ENST00000372801.5	Ensembl	ENSP00000361887.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Non-small cell lung cancer - Homo sapiens (human)
FoxO signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)

Biological Process

cell morphogenesis
branching involved in blood vessel morphogenesis
neural tube formation
positive regulation of protein phosphorylation
endocardium development

Molecular Function

magnesium ion binding
protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372806
Coding exons: 11
Length: 113486
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.47	197	264	0.746	0.0000137	3225
Missense (PolyPhen)		37	82.455	0.44873		984
Synonymous	0.383	85	89.6	0.949	0.00000463	879
Loss of Function	3.55	9	30.0	0.300	0.00000185	323

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes. {ECO:0000250|UniProtKB:Q9JI11, ECO:0000269|PubMed:11278283, ECO:0000269|PubMed:11517310, ECO:0000269|PubMed:12757711, ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:16510573, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18986304, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:21212262, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:8702870, ECO:0000269|PubMed:8816758}.;
Disease: DISEASE: T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations (TIIAC) [MIM:614868]: A primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T-cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect. {ECO:0000269|PubMed:22294732}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.526
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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