rs150185028
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_015340.4(LARS2):c.488G>A(p.Arg163His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. R163C) has been classified as Uncertain significance.
Frequency
Consequence
NM_015340.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.488G>A | p.Arg163His | missense_variant | 6/22 | ENST00000645846.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.488G>A | p.Arg163His | missense_variant | 6/22 | NM_015340.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152064Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251458Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135904
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461692Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727172
GnomAD4 genome ? AF: 0.000276 AC: 42AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74408
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 163 of the LARS2 protein (p.Arg163His). This variant is present in population databases (rs150185028, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with LARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 504793). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LARS2 protein function with a negative predictive value of 80%. 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 | Feb 01, 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 | May 18, 2017 | The p.Arg163His variant in LARS2 has not been previously reported in individuals with hearing loss or Perrault syndrome, but has been identified in 20/24032 Afr ican chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs150185028). Although this variant has been seen in the g eneral population, its frequency is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analyses suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, the clinical significance of the p.Arg 163His variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at