GeneBe

ATF6

protein-coding

activating transcription factor 6, the group of Basic leucine zipper proteins

Gene summary

This gene encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Although it is a transcription factor, this protein is unusual in that it is synthesized as a transmembrane protein that is embedded in the ER. It functions as an ER stress sensor/transducer, and following ER stress-induced proteolysis, it functions as a nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is present in the promoters of genes encoding ER chaperones. This protein has been identified as a survival factor for quiescent but not proliferative squamous carcinoma cells. There have been conflicting reports about the association of polymorphisms in this gene with diabetes in different populations, but another polymorphism has been associated with increased plasma cholesterol levels. This gene is also thought to be a potential therapeutic target for cystic fibrosis. [provided by RefSeq, Aug 2011]

MANE transcript

NM_007348.4

Inheritance

AR, AD

ClinVar variants

P:51U:251B:120

Top phenotype

Achromatopsia 7

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr1:161,766,298-161,977,574

External References & Databases

Ensembl (ENSG00000118217)NCBI Gene (22926)OMIM (605537)HGNC:791GenCCUniProt (P18850)AlphaFoldClinVar (ATF6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~211.3 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

achromatopsia 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014677

Submitter: PanelApp Australia

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

achromatopsiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018852

Submitter: Orphanet

achromatopsia 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014677

Submitter: Labcorp Genetics (formerly Invitae)

achromatopsia 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014677

Submitter: G2P

ATF6-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100447

Submitter: ClinGen

ATF6 was first reported in relation to autosomal recessive early-onset retinopathy and/or achromatopsia in 2015 (Xu et al., PMID: 26070061; Kohl et al., PMID: 26029869; Ansar et al., PMID: 26063662). The term ATF6-related retinopathy is used here to describe the disease entity associated with this gene. Achromatopsia is an early-onset retinal dystrophy characterized by impaired color vision, photophobia, nystagmus, reduced visual acuity. Additional features on ocular exam include foveal hypoplasia and cone photoreceptor dysfunction. Twelve variants (missense, frameshift, nonsense, splice site) that have been reported in sixteen probands in five publications (PMIDs: 26070061, 26029869; 26063662, 28041643, 31237654) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. For example, of note, two multi-exon deletions in ATF6 were reported by Lee et al. (PMID: 32271167) as causative for autosomal recessive achromatopsia in two families, though these variants were not scored as part of this curation. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by experimental evidence, including animal studies, expression studies, and in vitro functional assays (PMID: 26063662, 26029869, 26070061, 32271167, 28028229, 34561305). ATF6 has been shown to be expressed in mouse retina (PMID: 26070061). While wildtype ATF6 has been shown in vitro to have expression throughout the cytoplasm and localization to the ER, mutant ATF6 had significantly reduced localization in the cytoplasm (PMID: 26063662). In addition, ATF6 variants have been shown to impaired transcriptional activity in vitro (PMID: 32271167). Knockout Atf6 mice have functional deficits in photoreceptor cells (PMID: 26029869. However, the phenotype of Atf6 knock out mice does not completely recapitulate the features of human achromatopsia, as alterations in photoreceptor function are only seen at an older age in mice. Retinal organoids derived from human iPSCs with ATF6 variants are shown to have abnormal cone photoreceptor cells, lacking inner and outer segments, but typical rod photoreceptors (PMID: 34561305). In summary, ATF6 is definitively associated with autosomal recessive ATF6 retinopathy. 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 Retina GCEP on the meeting date 10/07/2021 (SOP Version #8). This gene-disease pair was originally evaluated by the General GCEP on 11/16/2016 and reevaluated by the Retina GCEP in 2021. As a result of this reevaluation, the classification changed. The original classification was Strong and it was re-classified to Definitive due to additional genetic and experimental evidence and the demonstration of evidence for this gene-disease relationship over six years. This classification was approved by the Retina GCEP on Oct 7, 2021.

Clinical Genomic Database (CGD)

Achromatopsia 7AR

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: 26029869; 26063662Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATF6 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 420
Inborn genetic diseasesTotal: 91
not specifiedTotal: 62
Achromatopsia 7Total: 25
ATF6-related disorderTotal: 18
Retinal dystrophyTotal: 8
AchromatopsiaTotal: 3
Bilateral sensorineural hearing impairmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007348.4. 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
6
clinvar
100
clinvar
2
clinvar
 108
missense
2
clinvar
2
clinvar
237
clinvar
15
clinvar
3
clinvar
 259
nonsense
11
clinvar
6
clinvar
2
clinvar
 19
start loss
1
clinvar
 1
frameshift
9
clinvar
5
clinvar
3
clinvar
 17
splice donor/acceptor (+/-2bp)
3
clinvar
12
clinvar
3
clinvar
 18
Total26252511155422

Highest pathogenic variant AF is 0.00006264801

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007348.4RefSeqNP_031374.216MANE Select
ENST00000367942.4EnsemblENSP00000356919.316MANE Select
NM_001410890.1RefSeqNP_001397819.116Standard
NM_001437597.1RefSeqNP_001424526.116Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
atf6Danio rerio

Structure: endoplasmic reticulum unfolded protein response

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • Alzheimer,s disease - Homo sapiens (human)
  • Sterol Regulatory Element-Binding Proteins (SREBP) signalling
  • Alzheimers Disease
  • Photodynamic therapy-induced unfolded protein response

Biological Process

  • eye development
  • regulation of transcription by RNA polymerase II
  • protein folding
  • signal transduction
  • visual perception

Molecular Function

  • transcription regulatory region sequence-specific DNA binding
  • RNA polymerase II regulatory region sequence-specific DNA binding
  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

  • Golgi membrane
  • nucleus
  • nuclear envelope
  • nucleoplasm
  • endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367942
Coding exons
16
Length
197777
Individuals with no LoFs
125714
Homozygous LoFs
0
Heterozygous LoFs
34
Defined
125748
p
0.000135
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5573233520.9170.00001774350
Missense (PolyPhen)8090.2270.886661148
Synonymous-0.4411361301.050.000006681323
Loss of Function3.001736.60.4650.00000192436

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000630.000062rare
Latino/Admixed American0.000180.00014rare
Ashkenazi Jewish00.0absent
East Asian0.0000550.000054rare
Finnish00.0absent
European (Non-Finnish)0.000170.00016rare
South Asian0.000300.00029rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transmembrane glycoprotein of the endoplasmic reticulum that functions as a transcription activator and initiates the unfolded protein response (UPR) during endoplasmic reticulum stress. Cleaved upon ER stress, the N-terminal processed cyclic AMP-dependent transcription factor ATF-6 alpha translocates to the nucleus where it activates transcription of genes involved in the UPR. Binds DNA on the 5'-CCAC[GA]-3'half of the ER stress response element (ERSE) (5'-CCAAT-N(9)-CCAC[GA]-3') and of ERSE II (5'- ATTGG-N-CCACG-3'). Binding to ERSE requires binding of NF-Y to ERSE. Could also be involved in activation of transcription by the serum response factor. May play a role in foveal development and cone function in the retina. {ECO:0000269|PubMed:10564271, ECO:0000269|PubMed:11158310, ECO:0000269|PubMed:11779464, ECO:0000269|PubMed:26029869}.;
Disease
DISEASE: Achromatopsia 7 (ACHM7) [MIM:616517]: A form of achromatopsia, an ocular stationary disorder due to the absence of functioning cone photoreceptors in the retina. It is characterized by total colorblindness, low visual acuity, photophobia and nystagmus. {ECO:0000269|PubMed:26029869, ECO:0000269|PubMed:26063662}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.280

Intolerance Scores

LoFtool
0.768
RVIS EVS
0.42
RVIS percentile EVS
77.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.986

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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