rs149378938
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Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_006295.3(VARS1):c.3355C>T(p.Arg1119Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
VARS1
NM_006295.3 missense
NM_006295.3 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 3.91
Genes affected
VARS1 (HGNC:12651): (valyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, VARS1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.943
PP5
?
Variant 6-31779470-G-A is Pathogenic according to our data. Variant chr6-31779470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VARS1 | NM_006295.3 | c.3355C>T | p.Arg1119Cys | missense_variant | 28/30 | ENST00000375663.8 | |
VARS1 | XM_005249362.3 | c.3358C>T | p.Arg1120Cys | missense_variant | 28/30 | ||
VARS1 | XM_047419296.1 | c.3358C>T | p.Arg1120Cys | missense_variant | 27/29 | ||
VARS1 | XM_047419297.1 | c.3355C>T | p.Arg1119Cys | missense_variant | 27/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VARS1 | ENST00000375663.8 | c.3355C>T | p.Arg1119Cys | missense_variant | 28/30 | 1 | NM_006295.3 | P1 | |
VARS1 | ENST00000463184.1 | n.511C>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000204 AC: 5AN: 244528Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133784
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460350Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726544
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 28, 2020 | The homozygous p.Arg1119Cys variant in VARS1 was identified by our study in collaboration with the Gleeson Lab in an individual with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (PMID: 30755602). Please note that this variant may also be submitted to ClinVar by the Gleeson Lab. This variant was reported in 3 total Egyptian individuals with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, segregated with disease in 2 affected relatives from 1 family (PMID: 30755602), and has been identified in 0.007% (1/14966) of African chromosomes, 0.005% (1/18238) of East Asian chromosomes, and 0.005% (1/21226) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149378938). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 559839). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the p.Arg1119Cys variant is pathogenic (PMID: 30755602). Multiple variants with the same function as p.Arg1119Cys variant have been reported in association with disease in the literature and the variant is located in a region of VARS1 that is essential to protein function, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30755602). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PM3 (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 20, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | research | Gleeson Lab, University of California San Diego - Department of Neuroscience | Jan 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at