rs781382275
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_015340.4(LARS2):āc.2278A>Gā(p.Ser760Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.000014 ( 0 hom. )
Consequence
LARS2
NM_015340.4 missense
NM_015340.4 missense
Scores
2
5
11
Clinical Significance
Conservation
PhyloP100: 5.49
Genes affected
LARS2 (HGNC:17095): (leucyl-tRNA synthetase 2, mitochondrial) This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27118248).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.2278A>G | p.Ser760Gly | missense_variant | 19/22 | ENST00000645846.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.2278A>G | p.Ser760Gly | missense_variant | 19/22 | NM_015340.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251408Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135874
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460940Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6AN XY: 726830
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
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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 | Oct 25, 2022 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 760 of the LARS2 protein (p.Ser760Gly). This variant is present in population databases (rs781382275, gnomAD 0.06%). 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: 228789). 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. 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 | Jun 27, 2022 | 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 | Dec 31, 2015 | The p.Ser760Gly variant in LARS2 has not been previously reported in individuals with hearing loss. It has been identified in 4/11572 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); however, i ts frequency is not high enough to rule out a pathogenic role. Computational pre diction tools and conservation analyses do not provide strong support for or aga inst an impact to the protein. In summary, the clinical significance of the p.Se r760Gly variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;.;.
Sift4G
Uncertain
D;D;D;.;.
Polyphen
P;P;P;P;P
Vest4
MutPred
Loss of disorder (P = 0.0853);Loss of disorder (P = 0.0853);.;Loss of disorder (P = 0.0853);Loss of disorder (P = 0.0853);
MVP
MPC
0.43
ClinPred
T
GERP RS
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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