6-31779433-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_006295.3(VARS1):āc.3392G>Cā(p.Arg1131Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,611,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
VARS1
NM_006295.3 missense
NM_006295.3 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 0.165
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the VARS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.6849 (below the threshold of 3.09). Trascript score misZ: 3.4812 (above the threshold of 3.09). GenCC associations: The gene is linked to combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VARS1 | NM_006295.3 | c.3392G>C | p.Arg1131Pro | missense_variant | 28/30 | ENST00000375663.8 | NP_006286.1 | |
VARS1 | XM_005249362.3 | c.3395G>C | p.Arg1132Pro | missense_variant | 28/30 | XP_005249419.1 | ||
VARS1 | XM_047419296.1 | c.3395G>C | p.Arg1132Pro | missense_variant | 27/29 | XP_047275252.1 | ||
VARS1 | XM_047419297.1 | c.3392G>C | p.Arg1131Pro | missense_variant | 27/29 | XP_047275253.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459470Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726154
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2022 | The c.3392G>C (p.R1131P) alteration is located in exon 28 (coding exon 27) of the VARS gene. This alteration results from a G to C substitution at nucleotide position 3392, causing the arginine (R) at amino acid position 1131 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of methylation at R1131 (P = 0.0196);
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