chr6-31779454-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_006295.3(VARS1):c.3371A>G(p.Asp1124Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
VARS1
NM_006295.3 missense
NM_006295.3 missense
Scores
2
5
11
Clinical Significance
Conservation
PhyloP100: 4.94
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 where missense usually causes diseases, VARS1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VARS1 | NM_006295.3 | c.3371A>G | p.Asp1124Gly | missense_variant | 28/30 | ENST00000375663.8 | |
VARS1 | XM_005249362.3 | c.3374A>G | p.Asp1125Gly | missense_variant | 28/30 | ||
VARS1 | XM_047419296.1 | c.3374A>G | p.Asp1125Gly | missense_variant | 27/29 | ||
VARS1 | XM_047419297.1 | c.3371A>G | p.Asp1124Gly | missense_variant | 27/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VARS1 | ENST00000375663.8 | c.3371A>G | p.Asp1124Gly | missense_variant | 28/30 | 1 | NM_006295.3 | P1 | |
VARS1 | ENST00000463184.1 | n.527A>G | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152026Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 244734Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133838
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460234Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 726458
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1124 of the VARS protein (p.Asp1124Gly). This variant is present in population databases (rs761497924, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with VARS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
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
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
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