rs200574045
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005548.3(KARS1):āc.1350G>Cā(p.Glu450Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,607,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E450A) has been classified as Uncertain significance.
Frequency
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KARS1 | NM_005548.3 | c.1350G>C | p.Glu450Asp | missense_variant | 11/14 | ENST00000302445.8 | |
KARS1 | NM_001130089.2 | c.1434G>C | p.Glu478Asp | missense_variant | 12/15 | ||
KARS1 | NM_001378148.1 | c.882G>C | p.Glu294Asp | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KARS1 | ENST00000302445.8 | c.1350G>C | p.Glu450Asp | missense_variant | 11/14 | 1 | NM_005548.3 | A1 | |
KARS1 | ENST00000319410.9 | c.1434G>C | p.Glu478Asp | missense_variant | 12/15 | 1 | P4 | ||
KARS1 | ENST00000568378.5 | c.147-2508G>C | intron_variant | 5 | |||||
KARS1 | ENST00000564578.5 | c.*893G>C | 3_prime_UTR_variant, NMD_transcript_variant | 11/14 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250912Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135674
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1455678Hom.: 0 Cov.: 28 AF XY: 0.00000690 AC XY: 5AN XY: 724698
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 01, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Glu478Asp var iant in KARS has not been previously reported in individuals with hearing loss, but has been identified in 1/66554 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200574045). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The glutamic acid (Glu) at position 478 is not conserved through species, with 2 mammals and >10 fish having an aspartic a cid (Asp) at this position, suggesting that this change may be tolerated. Addit ional computational prediction tools suggest that the p.Glu478Asp variant may no t impact the protein. In summary, while the clinical significance of the p.Glu47 8Asp variant is uncertain, the lack of conservation suggests that it is more lik ely to be benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2021 | 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 aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 320632). This variant has not been reported in the literature in individuals affected with KARS-related conditions. This variant is present in population databases (rs200574045, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 478 of the KARS protein (p.Glu478Asp). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at