rs201358272
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_002047.4(GARS1):c.1904C>G(p.Ser635Trp) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S635L) has been classified as Likely benign.
Frequency
Consequence
NM_002047.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GARS1 | NM_002047.4 | c.1904C>G | p.Ser635Trp | missense_variant, splice_region_variant | 16/17 | ENST00000389266.8 | |
GARS1 | NM_001316772.1 | c.1742C>G | p.Ser581Trp | missense_variant, splice_region_variant | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GARS1 | ENST00000389266.8 | c.1904C>G | p.Ser635Trp | missense_variant, splice_region_variant | 16/17 | 1 | NM_002047.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249178Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135206
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2020 | The p.S635W variant (also known as c.1904C>G) is located in coding exon 16 of the GARS gene. The serine at codon 635 is replaced by tryptophan, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 16. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at