rs1553635112
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_015340.4(LARS2):āc.1520C>Gā(p.Pro507Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,098 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 Likely pathogenic (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
LARS2
NM_015340.4 missense
NM_015340.4 missense
Scores
13
3
2
Clinical Significance
Conservation
PhyloP100: 7.56
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.905
PP5
?
Variant 3-45491797-C-G is Pathogenic according to our data. Variant chr3-45491797-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517248.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.1520C>G | p.Pro507Arg | missense_variant | 13/22 | ENST00000645846.2 | |
LARS2-AS1 | NR_048543.1 | n.517+3447G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.1520C>G | p.Pro507Arg | missense_variant | 13/22 | NM_015340.4 | P1 | ||
LARS2-AS1 | ENST00000442534.2 | n.517+3447G>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460918Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 726698
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 22, 2017 | The p.Pro507Arg variant in LARS2 has been identified by our laboratory in 1 indi vidual with hearing loss who was compound heterozygous for this variant and a li kely pathogenic LARS2 variant, and both variants segregated with hearing loss in an affected sibling. The variant was absent from large population studies. In a ddition, computational prediction tools and conservation analysis suggest the va riant may impact the protein. In summary, although additional studies are requir ed to fully establish its clinical significance, the p.Pro507Arg variant is like ly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;.
Sift4G
Pathogenic
D;D;D;.;.
Polyphen
D;D;D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);.;Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);
MVP
MPC
0.86
ClinPred
D
GERP RS
Varity_R
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