rs117041419
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005548.3(KARS1):c.170A>T(p.Asn57Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. N57S) has been classified as Benign.
Frequency
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.170A>T | p.Asn57Ile | missense_variant | 2/14 | ENST00000302445.8 | |
KARS1 | NM_001130089.2 | c.254A>T | p.Asn85Ile | missense_variant | 3/15 | ||
KARS1 | NM_001378148.1 | c.-299A>T | 5_prime_UTR_variant | 2/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KARS1 | ENST00000302445.8 | c.170A>T | p.Asn57Ile | missense_variant | 2/14 | 1 | NM_005548.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251330Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135850
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461700Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727160
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74318
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2023 | The c.254A>T (p.N85I) alteration is located in exon 3 (coding exon 2) of the KARS gene. This alteration results from a A to T substitution at nucleotide position 254, causing the asparagine (N) at amino acid position 85 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 03, 2017 | The p.Asn85Ile variant in KARS has not been previously reported in individuals w ith hearing loss, but has been identified in 1/30782 South Asian chromosome by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs117041419). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, the clinical significa nce of the p.Asn85Ile variant is uncertain. ACMG/AMP Criteria applied: PM2 (Rich ards 2015). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at