ATRX

ATRX chromatin remodeler, the group of RNA helicases

Basic information

Region (hg38): X:77504880-77786233

Previous symbols: [ "RAD54", "JMS", "MRX52" ]

Links

ENSG00000085224 ∙ NCBI:546 ∙ OMIM:300032 ∙ HGNC:886 ∙ Uniprot:P46100 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• alpha thalassemia-X-linked intellectual disability syndrome (Definitive), mode of inheritance: XL
• intellectual disability-hypotonic facies syndrome, X-linked, 1 (Moderate), mode of inheritance: XL
• alpha thalassemia-X-linked intellectual disability syndrome (Supportive), mode of inheritance: XL
• alpha thalassemia-X-linked intellectual disability syndrome (Definitive), mode of inheritance: XL
• alpha thalassemia-X-linked intellectual disability syndrome (Strong), mode of inheritance: XL
• ATR-X-related syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alpha-thalassemia/impaired intellectual development syndrome, X-linked; Intellectual disability-hypotonic facies syndrome, X-linked 1	XL	General	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	Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Renal	6267462; 6682021; 6711605; 3239563; 1684092; 7726225; 8644709; 10398237; 10398234; 11449489; 11050622; 10751095; 15508018; 16222662; 16100724; 16813605; 16955409; 16688741; 17579672; 19764021; 20301622; 22089611

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATRX gene.

• Alpha thalassemia-X-linked intellectual disability syndrome (23 variants)
• not provided (15 variants)
• Intellectual disability-hypotonic facies syndrome, X-linked, 1 (4 variants)
• ATRX-related disorder (2 variants)
• Alpha thalassemia-X-linked intellectual disability syndrome;Intellectual disability-hypotonic facies syndrome, X-linked, 1 (2 variants)
• Neoplasm (1 variants)
• ATR-X-related syndrome (1 variants)
• Adrenal cortex carcinoma (1 variants)
• Global developmental delay (1 variants)
• HP:0000062 (present);HP:0000252 (present);HP:0002669 (present);HP:0010864 (present);HP:0000028 (present) (1 variants)
• Inborn genetic diseases (1 variants)
• Intellectual disability-hypotonic facies syndrome, X-linked (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATRX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	636	42	684
missense	6	49	558	248	76	937
nonsense	13	11	1			25
start loss			2	1		3
frameshift	13	3	2			18
inframe indel		1	34	6	1	42
splice donor/acceptor (+/-2bp)	4	5	1			10
splice region	3	2	28	88	9	130
non coding	1		3	211	54	269
Total	37	69	607	1102	173

Highest pathogenic variant AF is 0.00000892

Variants in ATRX

This is a list of pathogenic ClinVar variants found in the ATRX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-77508138-G-A			Likely benign (Jul 10, 2018)
X-77508356-T-C		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Jun 13, 2024)
X-77508357-TG-T		Alpha thalassemia-X-linked intellectual disability syndrome	Uncertain significance (Dec 05, 2020)
X-77508362-T-A		Alpha thalassemia-X-linked intellectual disability syndrome	Uncertain significance (Oct 29, 2024)
X-77508376-C-T		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Feb 03, 2023)
X-77508391-C-T		Alpha thalassemia-X-linked intellectual disability syndrome	Conflicting classifications of pathogenicity (Dec 08, 2024)
X-77508394-A-G		Alpha thalassemia-X-linked intellectual disability syndrome • ATRX-related disorder	Benign (Oct 17, 2024)
X-77508395-T-C		Alpha thalassemia-X-linked intellectual disability syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 19, 2024)
X-77508398-G-A		Alpha thalassemia-X-linked intellectual disability syndrome	Benign (Feb 25, 2024)
X-77508398-G-C		Inborn genetic diseases • Acquired hemoglobin H disease;Intellectual disability-hypotonic facies syndrome, X-linked, 1;Alpha thalassemia-X-linked intellectual disability syndrome • Alpha thalassemia-X-linked intellectual disability syndrome	Conflicting classifications of pathogenicity (Oct 07, 2024)
X-77508399-G-A		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Jun 04, 2023)
X-77508401-G-T		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Jun 25, 2021)
X-77508402-T-A		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Mar 06, 2021)
X-77508405-T-C		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Nov 16, 2022)
X-77508408-A-G		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Aug 23, 2023)
X-77508409-C-T		Alpha thalassemia-X-linked intellectual disability syndrome • not specified	Likely benign (Nov 04, 2024)
X-77508417-T-C		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (May 05, 2022)
X-77508420-T-C		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (May 01, 2024)
X-77508422-G-A			Uncertain significance (Dec 11, 2023)
X-77508424-G-A			Uncertain significance (May 02, 2023)
X-77508429-C-T		Alpha thalassemia-X-linked intellectual disability syndrome	Benign (Sep 04, 2024)
X-77508430-A-G		Alpha thalassemia-X-linked intellectual disability syndrome	Likely benign (Sep 03, 2023)
X-77508434-C-A		not specified	Uncertain significance (Jul 09, 2020)
X-77508434-C-T			Uncertain significance (Nov 01, 2023)
X-77508435-AC-A			Pathogenic (Aug 07, 2012)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATRX	protein_coding	protein_coding	ENST00000373344	35	281347

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.88e-11	125711	0	9	125720	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.10	604	860	0.702	0.0000617	16613
Missense in Polyphen		122	360.46	0.33846		6761
Synonymous	-0.824	310	292	1.06	0.0000207	4376
Loss of Function	8.22	5	88.5	0.0565	0.00000723	1648

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000114	0.0000985
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000626	0.0000462
European (Non-Finnish)	0.0000738	0.0000528
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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 (Consensus)

Recessive Scores

• pRec: 0.563

Intolerance Scores

• loftool: 0.00517
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.75

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.859
• ghis: 0.569

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.978

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Atrx
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: meiotic spindle organization;DNA repair;DNA methylation;nucleosome assembly;DNA replication-independent nucleosome assembly;chromatin remodeling;regulation of transcription, DNA-templated;spermatogenesis;positive regulation of nuclear cell cycle DNA replication;DNA damage response, signal transduction by p53 class mediator;forebrain development;replication fork processing;positive regulation of telomere maintenance;post-embryonic forelimb morphogenesis;multicellular organism growth;positive regulation of transcription by RNA polymerase II;Sertoli cell development;chromosome organization involved in meiotic cell cycle;protein localization to chromosome, telomeric region;seminiferous tubule development;cellular response to hydroxyurea;regulation of histone H3-K9 trimethylation;negative regulation of telomeric RNA transcription from RNA pol II promoter;positive regulation of telomeric RNA transcription from RNA pol II promoter;negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric
• Cellular component: condensed nuclear chromosome, centromeric region;nuclear chromosome, telomeric region;nucleus;nucleoplasm;nuclear heterochromatin;pericentric heterochromatin;nuclear body;PML body;nuclear pericentric heterochromatin;telomeric heterochromatin;nuclear subtelomeric heterochromatin
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;chromatin binding;helicase activity;protein binding;ATP binding;DNA translocase activity;methylated histone binding;histone binding;metal ion binding;chromo shadow domain binding