GeneBe

ATRX

protein-coding

ATRX chromatin remodeler, the group of RNA helicases

Gene summary

The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2017]

Previous symbols:
  • RAD54
  • JMS
  • MRX52

MANE transcript

NM_000489.6

Inheritance

XL, XLR

ClinVar variants

P:161U:977B:1192

Top phenotype

Alpha-thalassemia/impaired intellectual development syndrome, X-linked; Intellectual disability-hypotonic facies syndrome, X-linked 1

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:77,504,880-77,786,233

External References & Databases

Ensembl (ENSG00000085224)NCBI Gene (546)OMIM (300032)HGNC:886GenCCUniProt (P46100)AlphaFoldClinVar (ATRX)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~281.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

alpha-thalassemia/impaired intellectual development syndrome, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010519

Submitter: G2P

alpha-thalassemia/impaired intellectual development syndrome, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010519

Submitter: Ambry Genetics

ATR-X-related syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0016980

Submitter: PanelApp Australia

intellectual disability-hypotonic facies syndrome, X-linked, 1MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010663

Submitter: Ambry Genetics

alpha-thalassemia/impaired intellectual development syndrome, X-linkedDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010519

Submitter: Natera

ATR-X-related syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0016980

Submitter: ClinGen

*ATRX*, which encodes a chromatin remodeler, was first reported in relation to X-linked ATR-X-related syndrome in 1995 (Gibbons et al., PMID: 7697714). X-linked alpha thalassaemia intellectual disability (ATR-X) syndrome in males is associated with profound intellectual disability, facial dysmorphism, genital abnormalities, and alpha thalassaemia. Alpha thalassaemia is observed in approximately 75% of affected individuals. Female carriers are typically unaffected, and have skewed X inactivation. Seven variants (2 missense, 2 nonsense, 1 frameshift, 1 canonical splice site, and 1 near splice site) that have been reported in 10 probands in 6 publications (PMIDs: 7697714, 10204841, 11559911, 20500465, 23681356, 24805811) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by two knockout mouse models, and a physical association with MECP2, involved in Rett syndrome (PMIDs: 15668733, 17296936, 20865721, 21209221). In summary, there is definitive evidence supporting the relationship between *ATRX* and ATR-X-related syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018. It was recurated on September 29, 2021, and as a result of this re-evaluation, the classification did not change.

alpha-thalassemia/impaired intellectual development syndrome, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010519

Submitter: Labcorp Genetics (formerly Invitae)

alpha-thalassemia/impaired intellectual development syndrome, X-linkedSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010519

Submitter: Orphanet

Clinical Genomic Database (CGD)

Alpha-thalassemia/impaired intellectual development syndrome, X-linked; Intellectual disability-hypotonic facies syndrome, X-linked 1XL

Manifestation: Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Renal

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: 6267462; 6682021; 6711605; 3239563; 1684092; 7726225; 8644709; 10398237; 10398234; 11449489; 11050622; 10751095; 15508018; 16222662; 16100724; 16813605; 16955409; 16688741; 17579672; 19764021; 20301622; 22089611Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATRX variants in ClinVar

33 Conditions Cataloged
Alpha thalassemia-X-linked intellectual disability syndromeTotal: 2225
not providedTotal: 620
Inborn genetic diseasesTotal: 256
not specifiedTotal: 222
ATRX-related disorderTotal: 125
Intellectual disability-hypotonic facies syndrome, X-linked, 1Total: 124
Acquired hemoglobin H diseaseTotal: 43
ATR-X-related syndromeTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000489.6. 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
1
clinvar
32
clinvar
705
clinvar
38
clinvar
 776
missense
16
clinvar
74
clinvar
858
clinvar
380
clinvar
69
clinvar
 1397
nonsense
15
clinvar
18
clinvar
20
clinvar
 53
start loss
1
clinvar
 1
frameshift
16
clinvar
7
clinvar
34
clinvar
 57
splice donor/acceptor (+/-2bp)
8
clinvar
6
clinvar
32
clinvar
 46
Total5610597710851072330

Highest pathogenic variant AF is 0.000012414063

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000489.6RefSeqNP_000480.335MANE Select
ENST00000373344.11EnsemblENSP00000362441.435MANE Select
NM_138270.5RefSeqNP_612114.234Standard
ENST00000395603.7EnsemblENSP00000378967.334Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • miR-targeted genes in epithelium - TarBase
  • miR-targeted genes in lymphocytes - TarBase
  • miR-targeted genes in muscle cell - TarBase
  • miR-targeted genes in squamous cell - TarBase
  • Pathways Affected in Adenoid Cystic Carcinoma

Biological Process

  • meiotic spindle organization
  • DNA repair
  • DNA methylation
  • nucleosome assembly
  • DNA replication-independent nucleosome assembly

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • chromatin binding
  • helicase activity
  • protein binding

Cellular Component

  • condensed nuclear chromosome, centromeric region
  • nuclear chromosome, telomeric region
  • nucleus
  • nucleoplasm
  • nuclear heterochromatin

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000373344
Coding exons
35
Length
281347
Individuals with no LoFs
125711
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125720
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.106048600.7020.000061716613
Missense (PolyPhen)122360.460.338466761
Synonymous-0.8243102921.060.00002074376
Loss of Function8.22588.50.05650.000007231648

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000770.000062rare
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000630.000046rare
European (Non-Finnish)0.0000740.000053rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in transcriptional regulation and chromatin remodeling. Facilitates DNA replication in multiple cellular environments and is required for efficient replication of a subset of genomic loci. Binds to DNA tandem repeat sequences in both telomeres and euchromatin and in vitro binds DNA quadruplex structures. May help stabilizing G-rich regions into regular chromatin structures by remodeling G4 DNA and incorporating H3.3- containing nucleosomes. Catalytic component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S- phase and telomeres, and the in vitro remodeling of H3.3- containing nucleosomes. Its heterochromatin targeting is proposed to involve a combinatorial readout of histone H3 modifications (specifically methylation states of H3K9 and H3K4) and association with CBX5. Involved in maintaining telomere structural integrity in embryonic stem cells which probably implies recruitment of CBX5 to telomers. Reports on the involvement in transcriptional regulation of telomeric repeat-containing RNA (TERRA) are conflicting; according to a report, it is not sufficient to decrease chromatin condensation at telomers nor to increase expression of telomeric RNA in fibroblasts (PubMed:24500201). May be involved in telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines. Acts as negative regulator of chromatin incorporation of transcriptionally repressive histone H2AFY, particularily at telomeres and the alpha-globin cluster in erythroleukemic cells. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, required for the chromatin occupancy of SMC1 and CTCTF within the H19 imprinting control region (ICR) and involved in esatblishment of histone tails modifications in the ICR. May be involved in brain development and facial morphogenesis. Binds to zinc-finger coding genes with atypical chromatin signatures and regulates its H3K9me3 levels. Forms a complex with ZNF274, TRIM28 and SETDB1 to facilitate the deposition and maintenance of H3K9me3 at the 3' exons of zinc- finger genes (PubMed:27029610). {ECO:0000269|PubMed:12953102, ECO:0000269|PubMed:14990586, ECO:0000269|PubMed:20504901, ECO:0000269|PubMed:20651253, ECO:0000269|PubMed:21029860, ECO:0000269|PubMed:22391447, ECO:0000269|PubMed:22829774, ECO:0000269|PubMed:24500201, ECO:0000269|PubMed:27029610}.;
Disease
DISEASE: Alpha-thalassemia mental retardation syndrome, X-linked (ATRX) [MIM:301040]: A disorder characterized by severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions. {ECO:0000269|PubMed:10204841, ECO:0000269|PubMed:10417298, ECO:0000269|PubMed:10660327, ECO:0000269|PubMed:10995512, ECO:0000269|PubMed:12116232, ECO:0000269|PubMed:14990586, ECO:0000269|PubMed:16955409, ECO:0000269|PubMed:21421568, ECO:0000269|PubMed:7697714, ECO:0000269|PubMed:8968741, ECO:0000269|PubMed:9043863, ECO:0000269|PubMed:9326931}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked, syndromic, with hypotonic facies 1 (MRXSHF1) [MIM:309580]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSHF1 is a syndromic mental retardation. Clinical features include severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects. {ECO:0000269|PubMed:10398237, ECO:0000269|PubMed:10751095, ECO:0000269|PubMed:11050622, ECO:0000269|PubMed:15565397, ECO:0000269|PubMed:16222662, ECO:0000269|PubMed:8630485}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:300448]: A disorder characterized by hypochromic, microcytic red blood cells, hemoglobin H detected in peripheral blood, and multilineage myelodysplasia. {ECO:0000269|PubMed:12858175}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.563

Intolerance Scores

LoFtool
0.00517
RVIS EVS
-0.93
RVIS percentile EVS
9.75

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.978

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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