rs199693918
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_015340.4(LARS2):c.2404+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,583,428 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
LARS2
NM_015340.4 splice_donor_region, intron
NM_015340.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0002333
2
Clinical Significance
Conservation
PhyloP100: -0.415
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 Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
Variant 3-45524112-C-T is Benign according to our data. Variant chr3-45524112-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228790.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000447 (64/1431262) while in subpopulation AMR AF= 0.00126 (56/44542). AF 95% confidence interval is 0.000993. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.2404+4C>T | splice_donor_region_variant, intron_variant | ENST00000645846.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.2404+4C>T | splice_donor_region_variant, intron_variant | NM_015340.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000235 AC: 59AN: 250630Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135436
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GnomAD4 exome AF: 0.0000447 AC: 64AN: 1431262Hom.: 0 Cov.: 24 AF XY: 0.0000364 AC XY: 26AN XY: 713986
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152166Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | This sequence change falls in intron 20 of the LARS2 gene. It does not directly change the encoded amino acid sequence of the LARS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199693918, gnomAD 0.2%). 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: 228790). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2016 | Variant classified as Uncertain Significance - Favor Benign. The c.2404+4C>T var iant in LARS2 has not been previously identified in individuals with hearing los s, but has been identified in 0.2% (17/11552) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199693918 ). This variant is located in the 5' splice region. Computational tools do not s uggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c .2404+4C>T variant is uncertain, the frequency and computational data suggest it is more likely to be benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at