RPS6KA3

ribosomal protein S6 kinase A3, the group of AGC family kinases|MAPK activated protein kinases

Basic information

Region (hg38): X:20149910-20267519

Previous symbols: [ "MRX19", "CLS" ]

Links

ENSG00000177189 ∙ NCBI:6197 ∙ OMIM:300075 ∙ HGNC:10432 ∙ Uniprot:P51812 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Coffin-Lowry syndrome (Strong), mode of inheritance: XL
• Coffin-Lowry syndrome (Supportive), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• symptomatic form of Coffin-Lowry syndrome in female carriers (Supportive), mode of inheritance: AD
• Coffin-Lowry syndrome (Definitive), mode of inheritance: XL
• intellectual disability, X-linked 19 (Strong), mode of inheritance: XL
• Coffin-Lowry syndrome (Strong), mode of inheritance: XL
• Coffin-Lowry syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Coffin-Lowry syndrome; Intellectual developmental disorder, X-linked 19	XL	Audiologic/Otolaryngologic; Cardiovascular; Neurologic	The condition can include premature death from cardiovascular complications, including cardiomyopathy, and surveillance (including with echocardiogram and electrocardiogram) may allow early medical management; The condition may include hearing deficits, and surveillance may be beneficial to enable interventions related to hearing and speech; Medical management of stimulus-induced drop attacks (eg, with valproate, clonazepam, or SSRIs) may be beneficial, as are measures to prevent injuries from related falls	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Neurologic	5581017; 5052411; 1133653; 146889; 7681250; 7943043; 9719387; 9832033; 9744638; 10528858; 10319851; 11160957; 12210291; 15214012; 16879200; 17100996; 17318637; 19888300; 20301520; 20637903; 21614984; 22009732; 22490425; 25044551

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RPS6KA3 gene.

• not provided (154 variants)
• Intellectual disability, X-linked 19;Coffin-Lowry syndrome (69 variants)
• Inborn genetic diseases (44 variants)
• Coffin-Lowry syndrome;Intellectual disability, X-linked 19 (41 variants)
• Coffin-Lowry syndrome (37 variants)
• not specified (16 variants)
• Intellectual disability, X-linked 19 (13 variants)
• RPS6KA3-related condition (5 variants)
• Intellectual disability (4 variants)
• See cases (2 variants)
• Global developmental delay (1 variants)
• Motor delay;Hirsutism (1 variants)
• 7 conditions (1 variants)
• 14 conditions (1 variants)
• RPS6KA3-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RPS6KA3 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	26	10	39
missense	5	20	71	6	2	104
nonsense	19	5				24
start loss						0
frameshift	20	5	1			26
inframe indel	1	3	1			5
splice donor/acceptor (+/-2bp)	10	7	1			18
splice region	2		7	6	4	19
non coding		1	4	35	27	67
Total	55	41	81	67	39

Variants in RPS6KA3

This is a list of pathogenic ClinVar variants found in the RPS6KA3 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-20155127-A-G			Benign (Nov 05, 2018)
X-20155416-G-A		Intellectual disability, X-linked 19;Coffin-Lowry syndrome • RPS6KA3-related disorder	Likely benign (Mar 12, 2022)
X-20155417-A-T		Coffin-Lowry syndrome	Uncertain significance (Feb 23, 2023)
X-20155417-A-AT		Inborn genetic diseases	Uncertain significance (Jun 29, 2021)
X-20155424-TA-T		Coffin-Lowry syndrome	Pathogenic (May 15, 2019)
X-20155428-A-G			Likely benign (Jul 18, 2017)
X-20155435-C-T		Coffin-Lowry syndrome • Intellectual disability • Inborn genetic diseases	Pathogenic/Likely pathogenic (Nov 02, 2022)
X-20155436-G-A		Coffin-Lowry syndrome • Intellectual disability, X-linked 19	Pathogenic/Likely pathogenic (Jun 02, 2023)
X-20155453-C-T		Intellectual disability, X-linked 19 • not specified • Coffin-Lowry syndrome • Intellectual disability • Intellectual disability, X-linked 19;Coffin-Lowry syndrome • Inborn genetic diseases • RPS6KA3-related disorder	Benign/Likely benign (Jan 31, 2024)
X-20155454-G-A		Inborn genetic diseases	Likely benign (Oct 26, 2023)
X-20155475-G-GTGAC		Coffin-Lowry syndrome;Intellectual disability, X-linked 19	Pathogenic (May 04, 2023)
X-20155476-TG-T		Coffin-Lowry syndrome	Pathogenic (Dec 01, 2002)
X-20155479-C-T		Coffin-Lowry syndrome;Intellectual disability, X-linked 19	Benign (Nov 13, 2023)
X-20155487-G-A			Uncertain significance (Jun 04, 2023)
X-20155503-T-C		Intellectual disability, X-linked 19;Coffin-Lowry syndrome	Likely benign (Jan 06, 2023)
X-20155519-C-T			Uncertain significance (Dec 30, 2021)
X-20155522-T-C		Coffin-Lowry syndrome	Pathogenic (Apr 20, 2023)
X-20155539-G-T		Intellectual disability, X-linked 19;Coffin-Lowry syndrome	Likely benign (Jul 06, 2023)
X-20155576-A-G			Benign (Aug 10, 2018)
X-20155892-C-T			Likely benign (Sep 18, 2018)
X-20156094-T-C		Coffin-Lowry syndrome;Intellectual disability, X-linked 19	Likely benign (Apr 29, 2022)
X-20156099-G-A		Intellectual disability, X-linked 19	Uncertain significance (Nov 29, 2022)
X-20156104-C-T		Intellectual disability, X-linked 19;Coffin-Lowry syndrome	Uncertain significance (Oct 17, 2022)
X-20156114-C-T		Intellectual disability, X-linked 19;Coffin-Lowry syndrome	Uncertain significance (Jun 22, 2023)
X-20156115-T-TA		Intellectual disability, X-linked 19;Coffin-Lowry syndrome	Pathogenic (Oct 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RPS6KA3	protein_coding	protein_coding	ENST00000379565	22	117495

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000510	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.52	64	275	0.233	0.0000201	4868
Missense in Polyphen		8	121.4	0.065899		2183
Synonymous	1.41	73	90.0	0.811	0.00000653	1383
Loss of Function	5.41	0	34.1	0.00	0.00000278	556

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR- independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation (By similarity). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA- EPHA2 signaling pathway controls cell migration (PubMed:26158630). {ECO:0000250|UniProtKB:P18654, ECO:0000269|PubMed:10436156, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:26158630, ECO:0000269|PubMed:8250835, ECO:0000269|PubMed:9770464}.
• Disease: DISEASE: Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. {ECO:0000269|PubMed:10094187, ECO:0000269|PubMed:10528858, ECO:0000269|PubMed:14986828, ECO:0000269|PubMed:15214012, ECO:0000269|PubMed:8955270, ECO:0000269|PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A non-syndromic form of mild to moderate mental retardation. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation. {ECO:0000269|PubMed:10319851, ECO:0000269|PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: mTOR signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);Thermogenesis - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Kit receptor signaling pathway;MAPK Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;EGF-EGFR Signaling Pathway;Cytoplasmic Ribosomal Proteins;Insulin Signaling;Developmental Biology;Signaling by GPCR;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signal Transduction;Recycling pathway of L1;Signaling by Interleukins;repression of pain sensation by the transcriptional regulator dream;signaling pathway from g-protein families;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;Senescence-Associated Secretory Phenotype (SASP);Cellular Senescence;Cellular responses to stress;Innate Immune System;Immune System;Fibroblast growth factor-1;Nuclear Events (kinase and transcription factor activation);Neuronal System;Cellular responses to external stimuli;IL-7 signaling;Signaling by NTRK1 (TRKA);CREB phosphorylation;Signaling by NTRKs;BDNF;ERK/MAPK targets;EGFR1;MAPK targets/ Nuclear events mediated by MAP kinases;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;ErbB1 downstream signaling;MyD88 dependent cascade initiated on endosome;Coregulation of Androgen receptor activity;JAK STAT pathway and regulation;EPO signaling;L1CAM interactions;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;RSK activation;CREB phosphorylation through the activation of Ras;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;Signaling by Receptor Tyrosine Kinases;VEGF;Gastrin-CREB signalling pathway via PKC and MAPK;G alpha (q) signalling events;GPCR downstream signalling;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;PDGFR-beta signaling pathway (Consensus)

Recessive Scores

• pRec: 0.646

Intolerance Scores

• rvis_EVS: 0.39
• rvis_percentile_EVS: 76.05

Haploinsufficiency Scores

• pHI: 0.723
• hipred: Y
• hipred_score: 0.816

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.573

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rps6ka3
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region 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); craniofacial phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); neoplasm; reproductive 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); skeleton phenotype

Zebrafish Information Network

• Gene name: rps6ka3a
• Affected structure: mid intestine epithelium
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: skeletal system development;toll-like receptor signaling pathway;apoptotic process;cell cycle;signal transduction;central nervous system development;peptidyl-serine phosphorylation;positive regulation of cell growth;response to lipopolysaccharide;intracellular signal transduction;negative regulation of apoptotic process;negative regulation of cysteine-type endopeptidase activity involved in apoptotic process;regulation of translation in response to stress;regulation of DNA-templated transcription in response to stress;positive regulation of cell differentiation;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleoplasm;cytosol
• Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;ribosomal protein S6 kinase activity;protein binding;ATP binding;kinase activity;protein kinase binding;cysteine-type endopeptidase inhibitor activity involved in apoptotic process