VARS1

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

Basic information

Region (hg38): 6:31777518-31795752

Previous symbols: [ "VARS2", "VARS" ]

Links

ENSG00000204394

∙ NCBI:7407 ∙ OMIM:192150 ∙ HGNC:12651 ∙ Uniprot:P26640 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

combined oxidative phosphorylation defect type 20 (Supportive), mode of inheritance: AR
neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (Definitive), mode of inheritance: AR
neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	AR	General	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	Craniofacial; Neurologic	26539891; 29691655

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VARS1 gene.

Inborn_genetic_diseases (176 variants)
Neurodevelopmental_disorder_with_microcephaly,_seizures,_and_cortical_atrophy (74 variants)
not_provided (69 variants)
VARS1-related_disorder (18 variants)
not_specified (5 variants)
Elevated_circulating_hepatic_transaminase_concentration (2 variants)
Generalized_hypotonia (2 variants)
Premature_birth (2 variants)
Intellectual_disability (2 variants)
Abnormal_brain_morphology (2 variants)
Delayed_speech_and_language_development (2 variants)
Secondary_microcephaly (1 variants)
Microcephaly (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VARS1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006295.3. 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			2 clinvar	26 clinvar	5 clinvar	33
missense	4 clinvar	16 clinvar	202 clinvar	13 clinvar	5 clinvar	240
nonsense	5 clinvar	4 clinvar	1 clinvar			10
start loss						0
frameshift	3 clinvar	2 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	1 clinvar			6
Total	14	25	207	39	10

Highest pathogenic variant AF is 0.00007502145

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VARS1	protein_coding	protein_coding	ENST00000375663	29	18436

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.80e-8	1.00	125634	0	114	125748	0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.68	577	789	0.731	0.0000509	8069
Missense in Polyphen		193	327.57	0.58919		3481
Synonymous	1.99	274	319	0.859	0.0000197	2679
Loss of Function	4.98	27	72.9	0.370	0.00000387	739

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000360	0.000356
Ashkenazi Jewish	0.000101	0.0000992
East Asian	0.000274	0.000272
Finnish	0.00229	0.00227
European (Non-Finnish)	0.000394	0.000378
Middle Eastern	0.000274	0.000272
South Asian	0.000133	0.000131
Other	0.000330	0.000326

dbNSFP

Source: dbNSFP

Disease: DISEASE: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) [MIM:617802]: An autosomal recessive neurodevelopmental disorder characterized by severe developmental delay, intellectual disability, severe microcephaly, and cortical atrophy. {ECO:0000269|PubMed:26539891}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Amino Acid metabolism;tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Valine, leucine and isoleucine degradation;Cytosolic tRNA aminoacylation (Consensus)

Recessive Scores

pRec: 0.0913

Intolerance Scores

loftool: 0.626
rvis_EVS: -0.33
rvis_percentile_EVS: 30.9

Haploinsufficiency Scores

pHI: 0.288
hipred: Y
hipred_score: 0.563
ghis: 0.509

Essentials

essential_gene_CRISPR: E
essential_gene_CRISPR2: E
essential_gene_gene_trap: E
gene_indispensability_pred: E
gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

Gene name: Vars
Phenotype

Zebrafish Information Network

Gene name: vars
Affected structure: head
Phenotype tag: abnormal
Phenotype quality: decreased size

Gene ontology

Biological process: tRNA aminoacylation for protein translation;valyl-tRNA aminoacylation;aminoacyl-tRNA metabolism involved in translational fidelity
Cellular component: cytosol
Molecular function: aminoacyl-tRNA editing activity;valine-tRNA ligase activity;protein binding;ATP binding