chr1-173850408-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_018122.5(DARS2):c.1273G>T(p.Glu425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,750 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
DARS2
NM_018122.5 stop_gained
NM_018122.5 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.18
Genes affected
DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-173850408-G-T is Pathogenic according to our data. Variant chr1-173850408-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1065.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-173850408-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DARS2 | NM_018122.5 | c.1273G>T | p.Glu425Ter | stop_gained | 13/17 | ENST00000649689.2 | |
DARS2 | NM_001365213.2 | c.1273G>T | p.Glu425Ter | stop_gained | 13/14 | ||
DARS2 | NM_001365212.1 | c.1192-2941G>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DARS2 | ENST00000649689.2 | c.1273G>T | p.Glu425Ter | stop_gained | 13/17 | NM_018122.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251328Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461750Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727164
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GnomAD4 genome ? Cov.: 30
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2007 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
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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