ATP7A

ATPase copper transporting alpha, the group of ATPase copper transporting

Basic information

Region (hg38): X:77910689-78050395

Previous symbols: [ "MNK" ]

Links

ENSG00000165240 ∙ NCBI:538 ∙ OMIM:300011 ∙ HGNC:869 ∙ Uniprot:Q04656 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked distal spinal muscular atrophy type 3 (Definitive), mode of inheritance: XLR
• Menkes disease (Definitive), mode of inheritance: XLR
• occipital horn syndrome (Strong), mode of inheritance: XL
• Menkes disease (Definitive), mode of inheritance: XL
• X-linked distal spinal muscular atrophy type 3 (Moderate), mode of inheritance: XL
• Menkes disease (Supportive), mode of inheritance: XL
• Hirschsprung disease (Supportive), mode of inheritance: AD
• occipital horn syndrome (Supportive), mode of inheritance: XL
• X-linked distal spinal muscular atrophy type 3 (Supportive), mode of inheritance: XL
• X-linked distal spinal muscular atrophy type 3 (Definitive), mode of inheritance: XL
• Menkes disease (Definitive), mode of inheritance: XL
• X-linked distal spinal muscular atrophy type 3 (Strong), mode of inheritance: XL
• Menkes disease (Strong), mode of inheritance: XL
• Menkes disease (Definitive), mode of inheritance: XL
• X-linked distal spinal muscular atrophy type 3 (Moderate), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Menkes disease	XL	Biochemical; Renal	With early diagnosis, daily copper injections may be beneficial (SQ injections before 10 days of life have been reported as resulting in improvement of neurologic outcome); Individuals may be prone to urinary tract infections, and measures such as antibiotic prophylaxis may be beneficial	Biochemical; Cardiovascular; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal	14472668; 5045346; 1218238; 953234; 6104292; 6140952; 4075564; 2839049; 2512453; 8490646; 8490647; 8490659; 8099605; 7842019; 8149649; 7887410; 8923001; 8528242; 9111998; 9138147; 9511979; 9894833; 14635105; 14985388; 15981243; 16630173; 17108763; 18256395; 19153371; 20652413; 20301586; 20170900; 22992316; 22711717; 22695177; 21221114

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP7A gene.

• not provided (280 variants)
• Menkes kinky-hair syndrome;Cutis laxa, X-linked;X-linked distal spinal muscular atrophy type 3 (267 variants)
• Menkes kinky-hair syndrome;X-linked distal spinal muscular atrophy type 3;Cutis laxa, X-linked (256 variants)
• X-linked distal spinal muscular atrophy type 3;Menkes kinky-hair syndrome;Cutis laxa, X-linked (238 variants)
• Menkes kinky-hair syndrome (236 variants)
• Cutis laxa, X-linked;Menkes kinky-hair syndrome;X-linked distal spinal muscular atrophy type 3 (162 variants)
• Inborn genetic diseases (150 variants)
• Cutis laxa, X-linked;X-linked distal spinal muscular atrophy type 3;Menkes kinky-hair syndrome (79 variants)
• X-linked distal spinal muscular atrophy type 3;Cutis laxa, X-linked;Menkes kinky-hair syndrome (68 variants)
• not specified (65 variants)
• Ehlers-Danlos syndrome (26 variants)
• X-linked distal spinal muscular atrophy type 3 (20 variants)
• Cutis laxa, X-linked (20 variants)
• ATP7A-related condition (7 variants)
• See cases (3 variants)
• Intellectual disability (2 variants)
• History of neurodevelopmental disorder (2 variants)
• Au-Kline syndrome (1 variants)
• ATP7A-realted disorder (1 variants)
• Charcot-Marie-Tooth disease (1 variants)
• Charcot-Marie-Tooth disease type 2 (1 variants)
• Menkes kinky-hair syndrome;Cutis laxa, X-linked (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP7A 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			3	297	22	322
missense	13	21	374	122	30	560
nonsense	42	14				56
start loss						0
frameshift	37	52	1			90
inframe indel	3		2			5
splice donor/acceptor (+/-2bp)	17	8	2			27
splice region	4	5	19	39	2	69
non coding	1		14	94	31	140
Total	113	95	396	513	83

Variants in ATP7A

This is a list of pathogenic ClinVar variants found in the ATP7A 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-77910803-T-C		not specified	Uncertain significance (Feb 08, 2013)
X-77910848-T-C		not specified	Likely benign (Jan 17, 2017)
X-77910848-T-G		not specified	Likely benign (Jan 11, 2017)
X-77910952-T-C			Benign (Jun 20, 2018)
X-77968926-G-A		not specified	Uncertain significance (May 30, 2023)
X-77968990-C-T		not specified	Conflicting classifications of pathogenicity (Apr 27, 2022)
X-77969089-C-T		not specified	Uncertain significance (Jul 07, 2022)
X-77969227-T-C		not specified	Uncertain significance (Apr 27, 2023)
X-77969275-G-A		not specified	Uncertain significance (Sep 25, 2023)
X-77969353-T-C		not specified	Uncertain significance (Aug 17, 2022)
X-77969382-C-T		Menkes kinky-hair syndrome	Benign (May 28, 2019)
X-77969383-G-T		not specified	Uncertain significance (Jan 25, 2023)
X-77969410-T-A		not specified	Uncertain significance (Nov 21, 2022)
X-77969470-T-C		not specified	Uncertain significance (Jan 24, 2023)
X-77969516-G-A			Likely benign (Feb 01, 2023)
X-77969598-C-T		not specified	Uncertain significance (Jan 24, 2024)
X-77969611-G-A		not specified	Uncertain significance (Sep 14, 2022)
X-77971632-G-C		ATP7A-related disorder	Likely benign (Jan 17, 2024)
X-77971647-T-C		Menkes kinky-hair syndrome;X-linked distal spinal muscular atrophy type 3;Cutis laxa, X-linked	Likely benign (Dec 27, 2023)
X-77971649-C-G		X-linked distal spinal muscular atrophy type 3;Menkes kinky-hair syndrome;Cutis laxa, X-linked	Likely benign (Nov 18, 2023)
X-77971655-T-C		Menkes kinky-hair syndrome;Cutis laxa, X-linked;X-linked distal spinal muscular atrophy type 3	Uncertain significance (Feb 02, 2023)
X-77971656-G-A		Cutis laxa, X-linked;Menkes kinky-hair syndrome;X-linked distal spinal muscular atrophy type 3 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 10, 2023)
X-77971658-G-A		Cutis laxa, X-linked;Menkes kinky-hair syndrome;X-linked distal spinal muscular atrophy type 3	Uncertain significance (May 21, 2019)
X-77971660-G-A		Menkes kinky-hair syndrome;Cutis laxa, X-linked;X-linked distal spinal muscular atrophy type 3	Likely benign (Oct 22, 2023)
X-77971662-G-C		X-linked distal spinal muscular atrophy type 3;Cutis laxa, X-linked;Menkes kinky-hair syndrome	Likely benign (Jun 13, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP7A	protein_coding	protein_coding	ENST00000341514	22	139699

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000167	125722	3	5	125730	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.53	448	549	0.816	0.0000395	9789
Missense in Polyphen		143	234.17	0.61068		4197
Synonymous	2.00	161	197	0.819	0.0000144	3053
Loss of Function	5.47	4	42.4	0.0942	0.00000324	761

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000219	0.000219
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000374	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plasma membrane where it functions in the efflux of copper from cells.
• Disease: DISEASE: Menkes disease (MNKD) [MIM:309400]: An X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency. MNKD results in progressive neurodegeneration and connective-tissue disturbances: focal cerebral and cerebellar degeneration, early growth retardation, peculiar hair, hypopigmentation, cutis laxa, vascular complications and death in early childhood. The clinical features result from the dysfunction of several copper-dependent enzymes. A mild form of the disease has been described, in which cerebellar ataxia and moderate developmental delay predominate. {ECO:0000269|PubMed:10079817, ECO:0000269|PubMed:10319589, ECO:0000269|PubMed:10401004, ECO:0000269|PubMed:11241493, ECO:0000269|PubMed:11350187, ECO:0000269|PubMed:15981243, ECO:0000269|PubMed:21667063, ECO:0000269|PubMed:22992316, ECO:0000269|PubMed:7977350, ECO:0000269|PubMed:8981948}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Occipital horn syndrome (OHS) [MIM:304150]: An X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities include occipital horns, short, broad clavicles, deformed radii, ulnae and humeri, narrowing of the rib cage, undercalcified long bones with thin cortical walls and coxa valga. {ECO:0000269|PubMed:11431706, ECO:0000269|PubMed:17108763, ECO:0000269|PubMed:21667063, ECO:0000269|PubMed:9246006}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Distal spinal muscular atrophy, X-linked, 3 (DSMAX3) [MIM:300489]: A neuromuscular disorder. Distal spinal muscular atrophy, also known as distal hereditary motor neuronopathy, represents a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:20170900}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mineral absorption - Homo sapiens (human);Platinum Pathway, Pharmacokinetics/Pharmacodynamics;Copper homeostasis;Ion influx/efflux at host-pathogen interface;Ion channel transport;Antimicrobial peptides;Innate Immune System;Immune System;Transport of small molecules;Ion transport by P-type ATPases (Consensus)

Intolerance Scores

• loftool: 0.0197
• rvis_EVS: 0.41
• rvis_percentile_EVS: 76.49

Haploinsufficiency Scores

• pHI: 0.217
• hipred: Y
• hipred_score: 0.629
• ghis: 0.535

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.491

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atp7a
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; immune system 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); limbs/digits/tail phenotype; pigmentation phenotype; reproductive system phenotype; 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); normal phenotype; 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); respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: atp7a
• Affected structure: melanocyte
• Phenotype tag: abnormal
• Phenotype quality: intensity

Gene ontology

• Biological process: blood vessel development;in utero embryonic development;liver development;blood vessel remodeling;regulation of oxidative phosphorylation;tryptophan metabolic process;catecholamine metabolic process;copper ion transport;cellular copper ion homeostasis;mitochondrion organization;lactation;locomotory behavior;response to iron(III) ion;response to manganese ion;response to zinc ion;detoxification of copper ion;regulation of gene expression;positive regulation of lamellipodium assembly;copper ion import;peptidyl-lysine modification;removal of superoxide radicals;cerebellar Purkinje cell differentiation;pyramidal neuron development;central nervous system neuron development;extracellular matrix organization;collagen fibril organization;hair follicle morphogenesis;negative regulation of iron ion transmembrane transport;cellular response to platelet-derived growth factor stimulus;T-helper cell differentiation;epinephrine metabolic process;norepinephrine metabolic process;dopamine metabolic process;serotonin metabolic process;positive regulation of catalytic activity;negative regulation of catalytic activity;pigmentation;skin development;positive regulation of cell size;elastic fiber assembly;lung alveolus development;neuron projection morphogenesis;positive regulation of epithelial cell proliferation;cartilage development;positive regulation of oxidoreductase activity;elastin biosynthetic process;copper ion export;cellular response to amino acid stimulus;cellular response to antibiotic;cellular response to cadmium ion;cellular response to cobalt ion;cellular response to copper ion;cellular response to iron ion;cellular response to lead ion;cellular response to hypoxia;ATP hydrolysis coupled cation transmembrane transport;positive regulation of response to wounding;positive regulation of vascular associated smooth muscle cell migration;regulation of cytochrome-c oxidase activity
• Cellular component: nucleus;late endosome;endoplasmic reticulum;Golgi apparatus;trans-Golgi network;cytosol;plasma membrane;microvillus;membrane;integral component of membrane;basolateral plasma membrane;apical plasma membrane;trans-Golgi network transport vesicle;secretory granule;phagocytic vesicle membrane;cell leading edge;brush border membrane;neuron projection;neuronal cell body;perikaryon;membrane raft;perinuclear region of cytoplasm
• Molecular function: copper-exporting ATPase activity;copper ion transmembrane transporter activity;copper ion binding;protein binding;ATP binding;superoxide dismutase copper chaperone activity;copper-dependent protein binding;copper-transporting ATPase activity;Rac GTPase binding;chaperone binding;cuprous ion binding