KARS1 (lysyl-tRNA synthetase 1)

Gene

• Entrez ID: 3735
• Gene name: Lysyl-tRNA synthetase 1
• Gene symbol: KARS1
• Synonyms (NCBI Gene): CMTRIB, DEAPLE, DFNB89, KARS, KARS2, KRS, LEPID
• Chromosome: 16
• Chromosome location: 16q23.1
• Summary: Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs77573084	G>A	Conflicting-interpretations-of-pathogenicity, benign-likely-benign	Coding sequence variant, missense variant
rs149772470	C>T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Coding sequence variant, missense variant
rs201650281	G>A	Likely-pathogenic, pathogenic	Missense variant, coding sequence variant
rs267607194	A>T	Pathogenic	Missense variant, coding sequence variant, 5 prime UTR variant
rs377697859	C>A,T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Intron variant
rs397514745	A>G	Pathogenic	Missense variant, 5 prime UTR variant, coding sequence variant
rs397514746	C>T	Pathogenic	Missense variant, coding sequence variant
rs587776688	->AA	Pathogenic	Frameshift variant, 5 prime UTR variant, coding sequence variant
rs772410450	A>C	Pathogenic	Coding sequence variant, missense variant
rs778748895	C>A,T	Pathogenic	Coding sequence variant, missense variant
rs1415687857	G>A	Likely-pathogenic, uncertain-significance	Missense variant, coding sequence variant
rs1555512658	G>A	Pathogenic	Missense variant, coding sequence variant
rs1567498374	G>-,GG	Pathogenic	Coding sequence variant, frameshift variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000049	Function	TRNA binding	IBA
GO:0000049	Function	TRNA binding	IEA
GO:0000049	Function	TRNA binding	NAS	10952987
GO:0000166	Function	Nucleotide binding	IEA
GO:0002276	Process	Basophil activation involved in immune response	IBA
GO:0002276	Process	Basophil activation involved in immune response	IEA
GO:0002276	Process	Basophil activation involved in immune response	IGI	19524539
GO:0002863	Process	Positive regulation of inflammatory response to antigenic stimulus	IDA	15851690
GO:0003676	Function	Nucleic acid binding	IEA
GO:0003877	Function	ATP:ADP adenylyltransferase activity	IBA
GO:0003877	Function	ATP:ADP adenylyltransferase activity	IDA	23159739
GO:0004812	Function	Aminoacyl-tRNA ligase activity	IEA
GO:0004824	Function	Lysine-tRNA ligase activity	IBA
GO:0004824	Function	Lysine-tRNA ligase activity	IDA	9278442, 10952987, 23159739
GO:0004824	Function	Lysine-tRNA ligase activity	IEA
GO:0005515	Function	Protein binding	IPI	16189514, 21220307, 21536907, 21900206, 21988832, 22386318, 23159739, 24212136, 24312579, 24983501, 25416956, 29997244, 31116475, 32296183, 32814053, 33961781
GO:0005524	Function	ATP binding	IEA
GO:0005576	Component	Extracellular region	IEA
GO:0005615	Component	Extracellular space	IDA	15851690
GO:0005634	Component	Nucleus	IDA	23159739
GO:0005634	Component	Nucleus	IEA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IBA
GO:0005737	Component	Cytoplasm	IEA
GO:0005739	Component	Mitochondrion	HTP	34800366
GO:0005739	Component	Mitochondrion	IBA
GO:0005739	Component	Mitochondrion	IDA	10952987
GO:0005739	Component	Mitochondrion	IEA
GO:0005759	Component	Mitochondrial matrix	TAS
GO:0005829	Component	Cytosol	IDA	19289464, 23159739
GO:0005829	Component	Cytosol	IEA
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IDA
GO:0005886	Component	Plasma membrane	IEA
GO:0006412	Process	Translation	IEA
GO:0006418	Process	TRNA aminoacylation for protein translation	IEA
GO:0006430	Process	Lysyl-tRNA aminoacylation	IBA
GO:0006430	Process	Lysyl-tRNA aminoacylation	IDA	9278442, 10952987, 23159739
GO:0006430	Process	Lysyl-tRNA aminoacylation	IEA
GO:0008033	Process	TRNA processing	NAS	10952987
GO:0010165	Process	Response to X-ray	IEA
GO:0015966	Process	Diadenosine tetraphosphate biosynthetic process	IBA
GO:0015966	Process	Diadenosine tetraphosphate biosynthetic process	IDA	23159739
GO:0015966	Process	Diadenosine tetraphosphate biosynthetic process	IEA
GO:0015966	Process	Diadenosine tetraphosphate biosynthetic process	IGI	19524539
GO:0016020	Component	Membrane	IEA
GO:0016597	Function	Amino acid binding	IEA
GO:0016740	Function	Transferase activity	IEA
GO:0016874	Function	Ligase activity	IEA
GO:0017101	Component	Aminoacyl-tRNA synthetase multienzyme complex	IBA
GO:0017101	Component	Aminoacyl-tRNA synthetase multienzyme complex	IDA	19131329
GO:0017101	Component	Aminoacyl-tRNA synthetase multienzyme complex	IEA
GO:0042802	Function	Identical protein binding	IPI	18272479, 21536907, 24212136
GO:0042803	Function	Protein homodimerization activity	IPI	23159739
GO:0043032	Process	Positive regulation of macrophage activation	IBA
GO:0043032	Process	Positive regulation of macrophage activation	IDA	15851690
GO:0045893	Process	Positive regulation of DNA-templated transcription	IEA
GO:0045893	Process	Positive regulation of DNA-templated transcription	IGI	19524539
GO:0070371	Process	ERK1 and ERK2 cascade	IEA
GO:0070371	Process	ERK1 and ERK2 cascade	IGI	19524539

Other IDs

• MIM: 601421
• HGNC: 6215
• e!Ensembl: ENSG00000065427

Protein

• UniProt ID: Q15046
• Protein name: Lysine--tRNA ligase (EC 2.7.7.-) (EC 6.1.1.6) (Lysyl-tRNA synthetase) (LysRS)
• Protein function: Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA (PubMed:18029264, PubMed:18272479, Pub
• PDB: 3BJU, 4DPG, 4YCU, 4YCW, 6CHD, 6ILD, 6ILH, 7EA9, 8HYR, 8XP4, 9DOW, 9DPA, 9DPB, 9DPL
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01336	tRNA_anti-codon	126 → 206	OB-fold nucleic acid binding domain	Domain
  PF00152	tRNA-synt_2	222 → 574	tRNA synthetases class II (D, K and N)	Domain

• Sequence:

  MAAVQAAEVKVDGSEPKLSKNELKRRLKAEKKVAEKEAKQKELSEKQLSQATAAATNHTT
  DNGVGPEEESVDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDH
  LTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGD
  IIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFV
  RQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAP
  ELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSG
  MVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETR
  KILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKE
  GLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYG
  LPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPEDKKENVATTDTLESTTVGTSV

• Sequence length: 597

Pathways

KEGG:

Aminoacyl-tRNA biosynthesis

Reactome:

Cytosolic tRNA aminoacylation
Mitochondrial tRNA aminoacylation

Associated diseases

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Abnormal cerebral white matter morphology	Likely pathogenic; Pathogenic	rs201650281	RCV000681462
Abnormal pyramidal sign	Likely pathogenic; Pathogenic	rs201650281	RCV000681462
Autosomal recessive nonsyndromic hearing loss 89	Pathogenic; Likely pathogenic	rs1299524768, rs201650281, rs760134437, rs778748895	RCV002204554 RCV000986183 RCV004555374 RCV000986182
Charcot-Marie-Tooth disease recessive intermediate B	Likely pathogenic; Pathogenic	rs201650281, rs267607194, rs587776688	RCV003147413 RCV000008647 RCV000008648
Congenital sensorineural hearing impairment	Likely pathogenic; Pathogenic	rs201650281	RCV000681462
Deafness, congenital, and adult-onset progressive leukoencephalopathy	Likely pathogenic; Pathogenic	rs201650281, rs1555512658, rs778748895	RCV001293662 RCV001293660 RCV001293658
Global developmental delay	Likely pathogenic; Pathogenic	rs2151809445, rs1567498374	RCV002226985 RCV000678489
Hearing loss, autosomal recessive	Likely pathogenic; Pathogenic	rs201650281	RCV004699121
Hypotonia	Pathogenic	rs1567498374	RCV000678489
KARS-related disorder	Likely pathogenic; Pathogenic	rs201650281	RCV001265601
KARS1-related disorder	Likely pathogenic; Pathogenic	rs201650281, rs1431954464, rs2507056779, rs761527468	RCV001526444 RCV004527905 RCV004536823 RCV004531073
Lactic acidosis	Pathogenic	rs1567498374	RCV000678489
LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS	Likely pathogenic; Pathogenic	rs201650281, rs778748895, rs1567498374, rs768349236, rs2082153181	RCV001293661 RCV001293659 RCV001293663 RCV001293665 RCV001293666
Leukoencephalopathy, progressive, infantile-onset, with or without deafness	Likely pathogenic; Pathogenic	rs201650281, rs1299184638, rs2507556167, rs2507056779, rs1370913867, rs774447299, rs761527468, rs770522582	RCV002463662 RCV003223482 RCV003323263 RCV005254809 RCV003322806 RCV002463798 RCV001293656 RCV001293657
Microcephaly	Likely pathogenic	rs2151809445	RCV002226985
Nystagmus	Likely pathogenic	rs2151809445	RCV002226985
Optic neuropathy	Likely pathogenic; Pathogenic	rs201650281	RCV000681462
Progressive cerebellar ataxia	Likely pathogenic; Pathogenic	rs201650281	RCV000681462
Seizure	Likely pathogenic	rs2151809445	RCV002226985
Sensorineural hearing loss disorder	Pathogenic	rs1567498374	RCV000678489

Unknown
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Charcot-Marie-Tooth disease	Benign; Uncertain significance	rs146955132, rs1597170012	RCV000789994 RCV000789690
Cholangiocarcinoma	Benign	rs370077957	RCV005868099
Colorectal cancer	Benign	rs370077957	RCV005870696
Familial cancer of breast	Benign; Likely benign	rs370077957, rs147548667	RCV005868097 RCV005903043
Hearing impairment	Conflicting classifications of pathogenicity	rs144274136, rs117188693, rs149772470	RCV001375243 RCV001375254 RCV001375150
Leukodystrophy	Conflicting classifications of pathogenicity	rs1415687857	RCV000856838
Malignant lymphoma, large B-cell, diffuse	Benign	rs370077957	RCV005870695
Malignant tumor of esophagus	Benign	rs370077957	RCV005868098 RCV005870693
Malignant tumor of urinary bladder	Likely benign	rs750616239, rs139268669	RCV005930016 RCV005931384
Nonpapillary renal cell carcinoma	Benign	rs370077957	RCV005870694
Nonsyndromic genetic hearing loss	Conflicting classifications of pathogenicity	rs397514745	RCV000627042
Thyroid cancer, nonmedullary, 1	Uncertain significance	rs370244075	RCV005920927
Uterine corpus endometrial carcinoma	Likely benign; Benign	rs76197636, rs370077957	RCV005915977 RCV005868100 RCV005871031

Associations from Text Mining
Disease Name	Relationship Type	References
Anemia	Associate	29875423
Anorchia	Associate	33260297
Carcinoma Hepatocellular	Associate	33084231
Cardiomyopathies	Associate	33260297
Charcot Marie Tooth Disease	Associate	20920668, 33478492
Creutzfeldt Jakob Syndrome	Associate	25149502
Deafness	Associate	30737337, 32048449
Developmental Disabilities	Associate	33478492
Hearing Loss	Associate	33478492, 35106950
Hearing Loss Sensorineural	Associate	31116475, 33260297, 33942428
Heart Failure	Associate	33478492
Hyperlactatemia	Associate	33260297
Hypertension Portal	Associate	33478492
Hypoalbuminemia	Stimulate	29875423
Hypokalemia Familial	Associate	29875423
Intracranial Arteriovenous Malformations	Associate	40551197
LEOPARD Syndrome	Associate	33478492
Leukodystrophy Metachromatic	Associate	30737337, 33260297, 33942428
Leukoencephalopathies	Associate	33478492
Lung Diseases	Associate	29875423
Microcephaly	Associate	33260297, 33478492
Mitochondrial Diseases	Associate	30737337, 33260297, 33478492
Neoplasms	Stimulate	33084231
Neoplastic Syndromes Hereditary	Associate	31404076
Nervous System Diseases	Associate	33942428
Neurologic Manifestations	Associate	23596069
Nonsyndromic Deafness	Associate	31116475, 35106950
Nonsyndromic sensorineural hearing loss	Associate	21181198
Optic Nerve Diseases	Associate	31116475
Ovarian Dysgenesis 2	Associate	30737337
Peripheral Nervous System Diseases	Associate	20920668, 33260297
Prion Diseases	Associate	25149502
Seizures	Associate	31618474, 33942428
Seminoma	Associate	36713456
Squamous Cell Carcinoma of Head and Neck	Associate	31315917