GeneBe

FLT1

protein-coding

fms related receptor tyrosine kinase 1, the group of I-set domain containing|Receptor tyrosine kinases

Gene summary

This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]

Previous symbols:
  • FLT

MANE transcript

NM_002019.4

Inheritance

—

ClinVar variants

U:138B:28

Top phenotype

Carcinoma of colon

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr13:28,300,346-28,495,145

External References & Databases

Ensembl (ENSG00000102755)NCBI Gene (2321)OMIM (165070)HGNC:3763GenCCUniProt (P17948)AlphaFoldClinVar (FLT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~194.8 kb
Loading mutation effect viewer...

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 FLT1 variants in ClinVar

6 Conditions Cataloged
not specifiedTotal: 123
not providedTotal: 23
Carcinoma of colonTotal: 9
Lung adenocarcinomaTotal: 6
FLT1-related disorderTotal: 4
Squamous cell carcinomaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002019.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
9
clinvar
7
clinvar
 19
missense
127
clinvar
11
clinvar
1
clinvar
 139
nonsense
2
clinvar
 2
start loss
0
frameshift
3
clinvar
 3
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total00138208166
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002019.4RefSeqNP_002010.230MANE Select
ENST00000282397.9EnsemblENSP00000282397.430MANE Select
NM_001159920.2RefSeqNP_001153392.113Standard
NM_001160030.2RefSeqNP_001153502.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
flt1Danio rerio

Structure: blood vessel endothelial cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • HIF-1 signaling pathway - Homo sapiens (human)
  • Rap1 signaling pathway - Homo sapiens (human)
  • Ras signaling pathway - Homo sapiens (human)

Biological Process

  • angiogenesis
  • sprouting angiogenesis
  • monocyte chemotaxis
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • positive regulation of cell population proliferation

Molecular Function

  • transmembrane receptor protein tyrosine kinase activity
  • vascular endothelial growth factor-activated receptor activity
  • protein binding
  • ATP binding
  • growth factor binding

Cellular Component

  • extracellular space
  • endosome
  • plasma membrane
  • integral component of plasma membrane
  • focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000282397
Coding exons
30
Length
194777
Individuals with no LoFs
125721
Homozygous LoFs
0
Heterozygous LoFs
27
Defined
125748
p
0.000107
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.456117210.8480.00004018820
Missense (PolyPhen)190285.860.664663511
Synonymous-0.07522702681.010.00001632517
Loss of Function6.571068.90.1450.00000351858

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish0.000400.00040rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000790.000079rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. {ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102, ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773, ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759, ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407, ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712, ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933, ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276, ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162, ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537}.;
Disease
DISEASE: Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages.; DISEASE: Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia.;

Recessive Scores

pRec
0.648

Intolerance Scores

LoFtool
0.463
RVIS EVS
-1.52
RVIS percentile EVS
3.44

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.956

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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