7-30599995-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The ENST00000389266.8(GARS1):​c.373G>C​(p.Glu125Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E125G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GARS1
ENST00000389266.8 missense

Scores

8
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96
Variant links:
Genes affected
GARS1 (HGNC:4162): (glycyl-tRNA synthetase 1) This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a helix (size 9) in uniprot entity GARS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000389266.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-30599995-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208650.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GARS1NM_002047.4 linkuse as main transcriptc.373G>C p.Glu125Gln missense_variant 3/17 ENST00000389266.8 NP_002038.2
GARS1NM_001316772.1 linkuse as main transcriptc.211G>C p.Glu71Gln missense_variant 3/17 NP_001303701.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkuse as main transcriptc.373G>C p.Glu125Gln missense_variant 3/171 NM_002047.4 ENSP00000373918 P2P41250-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 01, 2018A different missense substitution at this codon (p.Glu125Lys) has been determined to be pathogenic (PMID: 25356970). This suggests that the glutamic acid residue is critical for GARS protein function and that other missense substitutions at this position may also be pathogenic. This sequence change replaces glutamic acid with glutamine at codon 125 of the GARS protein (p.Glu125Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Uncertain
0.43
D
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.9
D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.022
D
Sift4G
Uncertain
0.016
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.40
Loss of ubiquitination at K129 (P = 0.0432);
MVP
0.86
MPC
1.1
ClinPred
0.97
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797044855; hg19: chr7-30639611; API