rs1345590827
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate
The NM_002047.4(GARS1):c.1421G>A(p.Arg474Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. R474P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002047.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GARS1 | NM_002047.4 | c.1421G>A | p.Arg474Gln | missense_variant | 11/17 | ENST00000389266.8 | |
GARS1 | NM_001316772.1 | c.1259G>A | p.Arg420Gln | missense_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GARS1 | ENST00000389266.8 | c.1421G>A | p.Arg474Gln | missense_variant | 11/17 | 1 | NM_002047.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249576Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135406
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GARS-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 474 of the GARS protein (p.Arg474Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at