GeneBe

KLF1

protein-coding

KLF transcription factor 1, the group of Kruppel like factors|Zinc fingers C2H2-type

Gene summary

This gene encodes a hematopoietic-specific transcription factor that induces high-level expression of adult beta-globin and other erythroid genes. The zinc-finger protein binds to the DNA sequence CCACACCCT found in the beta hemoglobin promoter. Heterozygous loss-of-function mutations in this gene result in the dominant In(Lu) blood phenotype. [provided by RefSeq, Oct 2009]

MANE transcript

NM_006563.5

Inheritance

AD, AR, BG

ClinVar variants

P:27U:126B:64

Top phenotype

Anemia, dyserythropoietic congenital, type IVa; Anemia, congenital dyserythropoietic, type Ivb; Blood group, Lutheran inhibitor

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr19:12,884,422-12,887,201

External References & Databases

Ensembl (ENSG00000105610)NCBI Gene (10661)OMIM (600599)HGNC:6345GenCCUniProt (Q13351)AlphaFoldClinVar (KLF1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~2.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

anemia, congenital dyserythropoietic, type IVaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013355

Submitter: Labcorp Genetics (formerly Invitae)

anemia, congenital dyserythropoietic, type IVaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013355

Submitter: Orphanet

hereditary persistence of fetal hemoglobin-beta-thalassemia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018749

Submitter: Orphanet

anemia, congenital dyserythropoietic, type IVaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013355

Submitter: Ambry Genetics

hereditary persistence of fetal hemoglobin-sickle cell disease syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016672

Submitter: Orphanet

anemia, congenital dyserythropoietic, type IVaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013355

Submitter: G2P

anemia, congenital dyserythropoietic, type IVaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013355

Submitter: PanelApp Australia

anemia, congenital dyserythropoietic, type IVbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0975829

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Anemia, dyserythropoietic congenital, type IVa; Anemia, congenital dyserythropoietic, type Ivb; Blood group, Lutheran inhibitorAD/AR/BG

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Treatments (including regular RBC transfusions and splenectomy) may be beneficial; Variants associated with a blood group may be important in specific situations (eg, related to transfusion)

Refs: 1659863; 7680924; 7521883; 17319831; 18487511; 21055716; 20676099; 21531944; 21821711; 21273267; 22093801; 22102705Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLF1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 174
Inborn genetic diseasesTotal: 40
Congenital dyserythropoietic anemia type 4Total: 27
KLF1-related disorderTotal: 24
BLOOD GROUP--LUTHERAN INHIBITORTotal: 17
not specifiedTotal: 13
Anemia, congenital dyserythropoietic, type IVbTotal: 9
FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 6Total: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006563.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
49
clinvar
 51
missense
7
clinvar
3
clinvar
117
clinvar
15
clinvar
 142
nonsense
5
clinvar
4
clinvar
5
clinvar
 14
start loss
1
clinvar
 1
frameshift
3
clinvar
3
clinvar
1
clinvar
 7
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total1512126640217

Highest pathogenic variant AF is 0.00010567565

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006563.5RefSeqNP_006554.13MANE Select
ENST00000264834.6EnsemblENSP00000264834.33MANE Select
ENST00000876185.1EnsemblENSP00000546244.13Standard
ENST00000876185.2EnsemblENSP00000546244.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Hematopoietic Stem Cell Differentiation

Biological Process

  • regulation of transcription, DNA-templated
  • regulation of transcription by RNA polymerase II
  • erythrocyte differentiation
  • positive regulation of transcription, DNA-templated
  • positive regulation of transcription by RNA polymerase II

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity
  • protein binding

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264834
Coding exons
3
Length
2759
Individuals with no LoFs
125626
Homozygous LoFs
0
Heterozygous LoFs
21
Defined
125647
p
0.0000836
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8511712050.8330.00001042198
Missense (PolyPhen)7293.3790.77105967
Synonymous0.6138996.70.9210.00000510795
Loss of Function1.26711.70.6015.05e-7118

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00012rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.000130.00012rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis. Is a dual regulator of fetal-to-adult globin switching. Binds to the CACCC box in the beta-globin gene promoter and acts as a preferential activator of this gene. Furthermore, it binds to the BCL11A promoter and activates expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. This dual activity ensures that, in most adults, fetal hemoglobin levels are low. Able to activate CD44 and AQP1 promoters. When sumoylated, acts as a transcriptional repressor by promoting interaction with CDH2/MI2beta and also represses megakaryocytic differentiation. {ECO:0000250|UniProtKB:P46099, ECO:0000269|PubMed:25585695}.;
Disease
DISEASE: Anemia, congenital dyserythropoietic, 4 (CDAN4) [MIM:613673]: A blood disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDA4 also have increased levels of fetal hemoglobin. {ECO:0000269|PubMed:21055716, ECO:0000269|PubMed:25585695}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.134

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.929

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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