GeneBe

HSF4

protein-coding

heat shock transcription factor 4

Gene summary

Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. HSF4 lacks the carboxyl-terminal hydrophobic repeat which is shared among all vertebrate HSFs and has been suggested to be involved in the negative regulation of DNA binding activity. Two alternatively spliced transcripts encoding distinct isoforms and possessing different transcriptional activity have been described. [provided by RefSeq, Jul 2008]

Previous symbols:
  • CTM

MANE transcript

NM_001374675.1

Inheritance

AD, AR

ClinVar variants

P:25U:117B:34

Top phenotype

Cataract 5, multiple types

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr16:67,164,681-67,169,945

External References & Databases

Ensembl (ENSG00000102878)NCBI Gene (3299)OMIM (602438)HGNC:5227GenCCUniProt (Q9ULV5)AlphaFoldClinVar (HSF4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract 5 multiple typesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007290

Submitter: G2P

cataract 5 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007290

Submitter: Labcorp Genetics (formerly Invitae)

cataract 5 multiple typesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007290

Submitter: PanelApp Australia

cataract 5 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007290

Submitter: PanelApp Australia

early-onset lamellar cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018611

Submitter: Orphanet

total early-onset cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021548

Submitter: Orphanet

cataract 5 multiple typesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007290

Submitter: G2P

Clinical Genomic Database (CGD)

Cataract 5, multiple typesAD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 3233780; 12089525; 18941546; 19014451; 20670914Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HSF4 variants in ClinVar

7 Conditions Cataloged
Cataract 5 multiple typesTotal: 95
Inborn genetic diseasesTotal: 72
not providedTotal: 35
HSF4-related disorderTotal: 31
not specifiedTotal: 9
Bilateral congenital or childhood onset cataractsTotal: 1
Developmental cataractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001374675.1. 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
9
clinvar
17
clinvar
1
clinvar
 27
missense
4
clinvar
4
clinvar
104
clinvar
13
clinvar
3
clinvar
 128
nonsense
3
clinvar
2
clinvar
1
clinvar
 6
start loss
0
frameshift
4
clinvar
3
clinvar
2
clinvar
 9
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
1
clinvar
 6
Total1213117304176

Highest pathogenic variant AF is 0.000071892966

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001374675.1RefSeqNP_001361604.113MANE Select
ENST00000521374.6EnsemblENSP00000430947.213MANE Select
NM_001040667.3RefSeqNP_001035757.113Standard
NM_001374674.1RefSeqNP_001361603.113Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hsf4Danio rerio

Structure: lens fiber cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • regulation of transcription, DNA-templated
  • visual perception
  • positive regulation of cell population proliferation
  • histone H3-K9 demethylation

Molecular Function

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

Cellular Component

  • nucleus
  • nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264009
Coding exons
13
Length
6561
Individuals with no LoFs
124772
Homozygous LoFs
0
Heterozygous LoFs
104
Defined
124876
p
0.000416
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6512512820.8910.00001513125
Missense (PolyPhen)6372.0230.87472881
Synonymous0.3361171220.9610.000006851043
Loss of Function1.161723.00.7390.00000105253

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000550.00051rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.00120.0012notable
Finnish0.000330.00028rare
European (Non-Finnish)0.000490.00046rare
South Asian0.000230.00020rare
Other0.000180.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: DNA-binding protein that specifically binds heat shock promoter elements (HSE). Isoform HSF4A represses transcription while the isoform HSF4B activates transcription. {ECO:0000269|PubMed:16371476}.;
Disease
DISEASE: Cataract 5, multiple types (CTRCT5) [MIM:116800]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT5 includes infantile, lamellar, zonular, nuclear, anterior polar, stellate, and Marner-type cataracts, among others. Finger malformation is observed in some kindreds. {ECO:0000269|PubMed:12089525, ECO:0000269|PubMed:16876512}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.125

Intolerance Scores

LoFtool
0.209
RVIS EVS
-0.27
RVIS percentile EVS
34.6

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.965

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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