rs763377687
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005548.3(KARS1):āc.1472T>Cā(p.Met491Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KARS1 | NM_005548.3 | c.1472T>C | p.Met491Thr | missense_variant | Exon 12 of 14 | ENST00000302445.8 | NP_005539.1 | |
KARS1 | NM_001130089.2 | c.1556T>C | p.Met519Thr | missense_variant | Exon 13 of 15 | NP_001123561.1 | ||
KARS1 | NM_001378148.1 | c.1004T>C | p.Met335Thr | missense_variant | Exon 12 of 14 | NP_001365077.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251456Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135900
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.0000591 AC XY: 43AN XY: 727230
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74392
ClinVar
Submissions by phenotype
not specified Uncertain:1
The c.1556T>C (p.M519T) alteration is located in exon 13 (coding exon 12) of the KARS gene. This alteration results from a T to C substitution at nucleotide position 1556, causing the methionine (M) at amino acid position 519 to be replaced by a threonine (T). Based on data from the NHLBI Exome Sequencing Project (ESP), the KARS c.1556T>C alteration was not observed among 6,498 individuals tested. The c.1556T>C alteration was observed in 1 out of 121,404 total alleles studied (0.0008%) in the Exome Aggregation Consortium (ExAC) Database. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). The p.M519 amino acid is conserved in available vertebrate species. The p.M519T alteration is predicted to be possibly damaging by Polyphen and tolerated by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the KARS c.1556T>C alteration was not observed among 6,498 individuals tested. The c.1556T>C alteration was observed in 1 out of 121,404 total alleles studied (0.0008%) in the Exome Aggregation Consortium (ExAC) Database. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). _x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution:_x000D_ The p.M519 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.M519T amino acid is located in the catalytic domain of the KARS protein. The function of the catalytic domain is to bind ATP, the tRNA acceptor stem, and to catalyze the aminoacylation reaction (Desogus, 2000). In silico prediction is conflicting:_x000D_ The p.M519T alteration is predicted to be possibly damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
KARS1: PM2, PP3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at