KARS1
lysyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class II
Basic information
Region (hg38): 16:75627474-75648643
Previous symbols: [ "DFNB89", "KARS" ]
Links
Phenotypes
GenCC
Source:
- 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:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Deafness, autosomal recessive 89; Deafness, congenital, and adult-onset progressive leukoencephalopathy; Leukoencephalopathy, progressive, infantile-onset, with or without deafness | 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; Gastrointestinal; Hematologic; Neurologic | 20920668; 23768514; 25330800; 28887846; 29615062; 30252186; 30715177; 30737337; 31116475; 33260297 |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (349 variants)
- not_specified (121 variants)
- KARS1-related_disorder (28 variants)
- Leukoencephalopathy,_progressive,_infantile-onset,_with_or_without_deafness (21 variants)
- Autosomal_recessive_nonsyndromic_hearing_loss_89 (17 variants)
- Charcot-Marie-Tooth_disease_recessive_intermediate_B (9 variants)
- Deafness,_congenital,_and_adult-onset_progressive_leukoencephalopathy (6 variants)
- LEUKOENCEPHALOPATHY,_PROGRESSIVE,_INFANTILE-ONSET,_WITH_DEAFNESS (5 variants)
- Inborn_genetic_diseases (3 variants)
- Global_developmental_delay (3 variants)
- Hearing_impairment (3 variants)
- Abnormal_pyramidal_sign (2 variants)
- Congenital_sensorineural_hearing_impairment (2 variants)
- Progressive_cerebellar_ataxia (2 variants)
- Optic_neuropathy (2 variants)
- Charcot-Marie-Tooth_disease (2 variants)
- Abnormal_cerebral_white_matter_morphology (2 variants)
- Sensorineural_hearing_loss_disorder (2 variants)
- Microcephaly (1 variants)
- Nonsyndromic_genetic_hearing_loss (1 variants)
- Hypotonia (1 variants)
- Hearing_loss,_autosomal_recessive (1 variants)
- Seizure (1 variants)
- Leukodystrophy (1 variants)
- Lactic_acidosis (1 variants)
- KARS-related_disorder (1 variants)
- Nystagmus (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. These statistics are base on transcript: NM_000005548.3. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 69 | 75 | ||||
| missense | 19 | 198 | 10 | 237 | ||
| nonsense | 8 | |||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 6 | |||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| Total | 16 | 26 | 203 | 79 | 7 |
Highest pathogenic variant AF is 0.00015923468
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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