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.

• Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (2 variants)
• not provided (2 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.

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				22	7	29
missense		9	108	5	7	129
nonsense	4	2	1			7
start loss						0
frameshift		1				1
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1			2
splice region			3	3	1	7
non coding			1	1		2
Total	4	13	111	28	14

Variants in VARS1

This is a list of pathogenic ClinVar variants found in the VARS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-31778987-G-A		Inborn genetic diseases	Uncertain significance (Mar 14, 2024)
6-31778998-G-T		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Uncertain significance (-)
6-31779005-T-C		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Uncertain significance (Feb 03, 2022)
6-31779029-G-A		Inborn genetic diseases	Uncertain significance (Feb 15, 2023)
6-31779037-C-T		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Uncertain significance (May 08, 2019)
6-31779038-G-A		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Uncertain significance (May 19, 2018)
6-31779043-C-T		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Uncertain significance (Sep 20, 2022)
6-31779044-G-A		VARS1-related disorder	Benign (Dec 13, 2019)
6-31779047-G-A		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Pathogenic (Dec 12, 2018)
6-31779070-C-T		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy • Inborn genetic diseases	Uncertain significance (Dec 21, 2022)
6-31779071-G-A		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Pathogenic/Likely pathogenic (Oct 24, 2023)
6-31779097-C-T		Inborn genetic diseases	Uncertain significance (Jun 03, 2022)
6-31779098-G-A		Inborn genetic diseases	Likely benign (Jan 25, 2024)
6-31779102-A-C			Likely benign (May 01, 2022)
6-31779114-C-T			Likely benign (Oct 01, 2022)
6-31779118-T-C		Inborn genetic diseases	Uncertain significance (May 18, 2023)
6-31779170-C-T		Inborn genetic diseases	Uncertain significance (Aug 19, 2024)
6-31779171-C-G		VARS1-related disorder • Inborn genetic diseases	Likely benign (Jun 16, 2022)
6-31779200-C-T		Inborn genetic diseases	Uncertain significance (Aug 27, 2024)
6-31779233-C-G		Inborn genetic diseases	Uncertain significance (Oct 07, 2024)
6-31779234-G-A			Benign/Likely benign (Sep 01, 2024)
6-31779261-G-A			Likely benign (May 01, 2023)
6-31779276-C-T		VARS1-related disorder	Likely benign (Aug 01, 2022)
6-31779433-C-G		Inborn genetic diseases	Uncertain significance (Sep 29, 2022)
6-31779439-C-T		Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy • Inborn genetic diseases	Uncertain significance (Apr 03, 2023)

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

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