CARS1

protein-coding

cysteinyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2010]

Previous symbols:

CARS

MANE transcript

NM_001014437.3

Inheritance

ClinVar variants

P:7U:158B:47

Top phenotype

Microcephaly, developmental delay, and brittle hair syndrome

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr11:3,000,922-3,057,613

External References & Databases

Ensembl (ENSG00000110619)

Transcript & Mutation Effects

hg38 • Region Span ~56.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly, developmental delay, and brittle hair syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030047

Submitter: G2P

microcephaly, developmental delay, and brittle hair syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030047

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Microcephaly, developmental delay, and brittle hair syndromeAR

Manifestation: Dermatologic; Endocrine; Gastrointestinal; Neurologic

Intervention: General

Rationale: 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

Refs: 30824121

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CARS1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 173

not providedTotal: 31

Microcephaly, developmental delay, and brittle hair syndromeTotal: 17

CARS1-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001014437.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	28 clinvar	4 clinvar	34
missense	2 clinvar	2 clinvar	150 clinvar	13 clinvar	2 clinvar	169
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	5	2	158	41	6	212

Highest pathogenic variant AF is 0.000022857203

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001014437.3	RefSeq	NP_001014437.1	23	MANE Select
ENST00000380525.9	Ensembl	ENSP00000369897.4	23	MANE Select
NM_001194997.2	RefSeq	NP_001181926.1	23	Standard
NM_001378136.1	RefSeq	NP_001365065.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cars	Danio rerio	Structure: skeletal muscle Quality: degenerate abnormal

Gene / Model

Organism

Observed Phenotype

cars

Danio rerio

Structure: skeletal muscle

Quality: degenerate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Beta-mercaptolactate-cysteine disulfiduria
Cysteine Metabolism
Cystinosis, ocular nonnephropathic
tRNA Aminoacylation

Biological Process

tRNA aminoacylation for protein translation
cysteinyl-tRNA aminoacylation

Molecular Function

tRNA binding
cysteine-tRNA ligase activity
protein binding
ATP binding
protein homodimerization activity

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380525
Coding exons: 23
Length: 56692
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	411	485	0.847	0.0000287	5472
Missense (PolyPhen)		125	168.76	0.74071		1909
Synonymous	0.303	190	195	0.972	0.0000128	1522
Loss of Function	4.31	15	46.8	0.321	0.00000216	573

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00018	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Note=A chromosomal aberration involving CARS is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with ALK.;

Recessive Scores

pRec: 0.233

Intolerance Scores

LoFtool: 0.794
RVIS EVS: -0.39
RVIS percentile EVS: 27.03

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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