16-75629518-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005548.3(KARS1):āc.1448C>Gā(p.Thr483Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,614,018 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
Genomes: š 0.000092 ( 0 hom., cov: 33)
Exomes š: 0.000097 ( 0 hom. )
Consequence
KARS1
NM_005548.3 missense
NM_005548.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 9.97
Genes affected
KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.824
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KARS1 | NM_005548.3 | c.1448C>G | p.Thr483Ser | missense_variant | 12/14 | ENST00000302445.8 | |
KARS1 | NM_001130089.2 | c.1532C>G | p.Thr511Ser | missense_variant | 13/15 | ||
KARS1 | NM_001378148.1 | c.980C>G | p.Thr327Ser | missense_variant | 12/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KARS1 | ENST00000302445.8 | c.1448C>G | p.Thr483Ser | missense_variant | 12/14 | 1 | NM_005548.3 | A1 | |
KARS1 | ENST00000319410.9 | c.1532C>G | p.Thr511Ser | missense_variant | 13/15 | 1 | P4 | ||
KARS1 | ENST00000568378.5 | c.147-1529C>G | intron_variant | 5 | |||||
KARS1 | ENST00000564578.5 | c.*991C>G | 3_prime_UTR_variant, NMD_transcript_variant | 12/14 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251440Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135890
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GnomAD4 exome AF: 0.0000971 AC: 142AN: 1461770Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66AN XY: 727196
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GnomAD4 genome AF: 0.0000920 AC: 14AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2022 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 511 of the KARS protein (p.Thr511Ser). This variant is present in population databases (rs200645820, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with KARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 504855). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2016 | The p.Thr511Ser variant in KARS has not been reported in individuals with hearin g loss, but has been identified in 10/66720 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200645820). Computational prediction tools and conservation analyses do not provide strong s upport for or against an impact to the protein. In summary, the clinical signifi cance of the p.Thr511Ser variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;P
Vest4
MutPred
0.61
.;Gain of helix (P = 0.0199);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at