KARS1

lysyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class II

Basic information

Region (hg38): 16:75627473-75648643

Previous symbols: [ "DFNB89", "KARS" ]

Links

ENSG00000065427 ∙ NCBI:3735 ∙ OMIM:601421 ∙ HGNC:6215 ∙ Uniprot:Q15046 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease recessive intermediate B (Supportive), mode of inheritance: AR
• leukoencephalopathy, progressive, infantile-onset, with or without deafness (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 89 (Limited), mode of inheritance: AR
• Charcot-Marie-Tooth disease recessive intermediate B (Limited), mode of inheritance: Unknown
• autosomal recessive nonsyndromic hearing loss 89 (Strong), mode of inheritance: AR
• leukoencephalopathy, progressive, infantile-onset, with or without deafness (Strong), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 89; Deafness, congenital, and adult-onset progressive leukoencephalopathy	AR	Audiologic/Otolaryngologic	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	Audiologic/Otolaryngologic; Neurologic	20920668; 23768514; 28887846; 30737337; 31116475

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KARS1 gene.

• not provided (308 variants)
• not specified (35 variants)
• Inborn genetic diseases (15 variants)
• Autosomal recessive nonsyndromic hearing loss 89 (12 variants)
• Leukoencephalopathy, progressive, infantile-onset, with or without deafness (12 variants)
• Charcot-Marie-Tooth disease recessive intermediate B (7 variants)
• Hearing impairment (3 variants)
• KARS1-related condition (3 variants)
• Deafness, congenital, and adult-onset progressive leukoencephalopathy (3 variants)
• LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS (2 variants)
• Progressive cerebellar ataxia;Abnormal cerebral white matter morphology;Abnormal pyramidal sign;Congenital sensorineural hearing impairment;Optic neuropathy (1 variants)
• Microcephaly;Seizure;Nystagmus;Global developmental delay (1 variants)
• Autosomal recessive nonsyndromic hearing loss 89;Leukoencephalopathy, progressive, infantile-onset, with or without deafness (1 variants)
• Global developmental delay;Leukodystrophy;Sensorineural hearing loss disorder (1 variants)
• KARS-related disorders (1 variants)
• KARS1-related disorder (1 variants)
• Nonsyndromic genetic hearing loss (1 variants)
• Autosomal recessive nonsyndromic hearing loss 89;Charcot-Marie-Tooth disease recessive intermediate B;Leukoencephalopathy, progressive, infantile-onset, with or without deafness;Deafness, congenital, and adult-onset progressive leukoencephalopathy (1 variants)
• Charcot-Marie-Tooth disease (1 variants)
• KARS1-Related Disorders (1 variants)
• Optic neuropathy;Abnormal pyramidal sign;Congenital sensorineural hearing impairment;Progressive cerebellar ataxia;Abnormal cerebral white matter morphology (1 variants)
• Charcot-Marie-Tooth disease recessive intermediate B;Autosomal recessive nonsyndromic hearing loss 89;Leukoencephalopathy, progressive, infantile-onset, with or without deafness;Deafness, congenital, and adult-onset progressive leukoencephalopathy (1 variants)
• Global developmental delay;Autosomal recessive nonsyndromic hearing loss 89;Leukodystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KARS1 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				52	5	57
missense	1	6	127	4	4	142
nonsense	1	4				5
start loss			2			2
frameshift	1	1				2
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1		1			2
splice region			10	14	4	28
non coding			2	59	28	89
Total	4	11	134	115	37

Highest pathogenic variant AF is 0.0000263

Variants in KARS1

This is a list of pathogenic ClinVar variants found in the KARS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-75627836-C-T			Likely benign (Mar 31, 2019)
16-75627862-C-T			Likely benign (Jul 11, 2018)
16-75627869-G-C			Likely benign (Jul 17, 2018)
16-75627905-G-C		not specified • Autosomal recessive nonsyndromic hearing loss 89	Benign (Jan 29, 2024)
16-75627907-G-A		KARS1-related disorder	Benign (Nov 07, 2023)
16-75627936-T-A			Uncertain significance (Oct 16, 2023)
16-75627936-T-C			Uncertain significance (Oct 28, 2022)
16-75627937-G-C		KARS1-related disorder	Likely benign (Jul 12, 2022)
16-75627943-TA-CT			Uncertain significance (Mar 14, 2022)
16-75627947-T-G		not specified	Likely benign (Jun 02, 2020)
16-75627951-CCTT-C		not specified	Uncertain significance (Jul 13, 2022)
16-75627955-C-G			Uncertain significance (Jul 16, 2022)
16-75627963-C-T			Uncertain significance (Dec 06, 2022)
16-75627964-G-A			Benign (Feb 03, 2022)
16-75627965-G-C			Uncertain significance (Feb 09, 2022)
16-75627973-G-A			Likely benign (Jun 14, 2022)
16-75627978-G-A			Uncertain significance (May 15, 2023)
16-75627982-C-G			Likely benign (Jun 15, 2018)
16-75627985-A-G			Likely benign (Apr 16, 2018)
16-75627987-G-A		LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS	Pathogenic (Mar 01, 2021)
16-75627995-T-G		Autosomal recessive nonsyndromic hearing loss 89	Pathogenic (Feb 14, 2022)
16-75628004-T-C			Likely benign (Nov 27, 2023)
16-75628014-C-T			Likely benign (Jul 28, 2020)
16-75628322-C-T			Benign (Dec 17, 2018)
16-75628381-AG-A			Benign (Nov 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KARS1	protein_coding	protein_coding	ENST00000319410	14	20920

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.21e-9	0.943	125719	0	29	125748	0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.727	380	342	1.11	0.0000199	4145
Missense in Polyphen		113	126.2	0.89541		1600
Synonymous	-2.13	153	123	1.24	0.00000691	1175
Loss of Function	1.96	18	29.5	0.610	0.00000161	373

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000271	0.000271
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000114	0.000114
Middle Eastern	0.000163	0.000163
South Asian	0.0000980	0.0000980
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: 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:9278442, PubMed:18029264, PubMed:18272479). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (PubMed:15851690). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:5338216, PubMed:14975237, PubMed:19524539, PubMed:23159739). {ECO:0000269|PubMed:14975237, ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:18029264, ECO:0000269|PubMed:19524539, ECO:0000269|PubMed:28887846, ECO:0000269|PubMed:5338216, ECO:0000269|PubMed:9278442}.
• Disease: DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:20920668}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]: A form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies. {ECO:0000269|PubMed:23768514, ECO:0000269|PubMed:28887846}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);tRNA Aminoacylation;Translation;Metabolism of proteins;Metabolism of amino acids and derivatives;Metabolism;tRNA charging;Selenoamino acid metabolism;Lysine metabolism;SeMet incorporation into proteins;Cytosolic tRNA aminoacylation;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.351

Intolerance Scores

• loftool: 0.342
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.68

Haploinsufficiency Scores

• pHI: 0.382
• hipred: Y
• hipred_score: 0.704
• ghis: 0.639

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.914

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kars
• Phenotype: craniofacial 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); skeleton phenotype

Zebrafish Information Network

• Gene name: kars
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: degenerate

Gene ontology

• Biological process: activation of MAPK activity;basophil activation involved in immune response;positive regulation of cytokine secretion involved in immune response;tRNA aminoacylation for protein translation;lysyl-tRNA aminoacylation;tRNA processing;negative regulation of cell population proliferation;response to X-ray;positive regulation of macrophage chemotaxis;diadenosine tetraphosphate biosynthetic process;viral process;tumor necrosis factor-mediated signaling pathway;positive regulation of macrophage activation;positive regulation of transcription, DNA-templated;ERK1 and ERK2 cascade;positive regulation of ERK1 and ERK2 cascade;positive regulation of cytokine production involved in inflammatory response;positive regulation of p38MAPK cascade;positive regulation of metallopeptidase activity
• Cellular component: extracellular space;nucleus;mitochondrion;mitochondrial matrix;cytosol;plasma membrane;aminoacyl-tRNA synthetase multienzyme complex
• Molecular function: tRNA binding;ATP adenylyltransferase activity;lysine-tRNA ligase activity;protein binding;ATP binding;amino acid binding;identical protein binding;protein homodimerization activity