STAT4

protein-coding

signal transducer and activator of transcription 4, the group of SH2 domain containing

Gene summary

The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

MANE transcript

NM_003151.4

Inheritance

ClinVar variants

P:2U:223B:133

Top phenotype

Disabling pansclerotic morphea of childhood

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr2:191,029,576-191,178,435

External References & Databases

Ensembl (ENSG00000138378)

Transcript & Mutation Effects

hg38 • Region Span ~148.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

disabling pansclerotic morphea of childhoodLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957497

Submitter: Ambry Genetics

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

disabling pansclerotic morphea of childhoodSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957497

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Disabling pansclerotic morphea of childhoodAD

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: The condition involves multisystem sequelae, including cytopenias, fibrosis, hypogammaglobulinemi, poor wound healing, and squamous-cell carcinoma, and surveillance for complications as well as medical management (eg, with the JAK inhibitor ruxolitinib) has been reported as beneficial

Refs: 37256972

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STAT4 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 487

not specifiedTotal: 51

STAT4-related disorderTotal: 17

Disabling pansclerotic morphea of childhoodTotal: 4

Systemic lupus erythematosus, susceptibility to, 11Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003151.4. 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	115 clinvar	4 clinvar	125
missense	1 clinvar	1 clinvar	205 clinvar	13 clinvar	1 clinvar	221
nonsense			4 clinvar			4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	1	1	223	128	5	358

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003151.4	RefSeq	NP_003142.1	23	MANE Select
ENST00000392320.7	Ensembl	ENSP00000376134.2	23	MANE Select
NM_001243835.2	RefSeq	NP_001230764.1	23	Standard
ENST00000358470.8	Ensembl	ENSP00000351255.4	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Jak-STAT signaling pathway - Homo sapiens (human)
Inflammatory bowel disease (IBD) - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
Th1 and Th2 cell differentiation - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)

Biological Process

JAK-STAT cascade
cytokine-mediated signaling pathway
interleukin-12-mediated signaling pathway
interleukin-21-mediated signaling pathway
interleukin-23-mediated signaling pathway

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein binding
identical protein binding

Cellular Component

nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392320
Coding exons: 23
Length: 122021
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.74	237	389	0.609	0.0000191	4951
Missense (PolyPhen)		56	136.98	0.40882		1771
Synonymous	1.25	120	139	0.864	0.00000736	1347
Loss of Function	5.15	10	48.8	0.205	0.00000239	577

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000070	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Carries out a dual function: signal transduction and activation of transcription. Involved in IL12 signaling.;
Disease: DISEASE: Systemic lupus erythematosus 11 (SLEB11) [MIM:612253]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:17804842, ECO:0000269|PubMed:19109131}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:17804842}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.262

Intolerance Scores

LoFtool: 0.339
RVIS EVS: -0.14
RVIS percentile EVS: 43.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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