chr1-173850408-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_018122.5(DARS2):​c.1273G>T​(p.Glu425*) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E425null) has been classified as Pathogenic. 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

Scores

2
2
3

Clinical Significance

Uncertain significance criteria provided, single submitter P:3U:1

Conservation

PhyloP100: 1.18

Publications

7 publications found
Variant links:
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]
DARS2 Gene-Disease associations (from GenCC):
  • leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS2NM_018122.5 linkc.1273G>T p.Glu425* stop_gained Exon 13 of 17 ENST00000649689.2 NP_060592.2 Q6PI48Q9H9J7
DARS2NM_001365213.2 linkc.1273G>T p.Glu425* stop_gained Exon 13 of 14 NP_001352142.1
DARS2NM_001365212.1 linkc.1192-2941G>T intron_variant Intron 12 of 15 NP_001352141.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DARS2ENST00000649689.2 linkc.1273G>T p.Glu425* stop_gained Exon 13 of 17 NM_018122.5 ENSP00000497569.1 Q6PI48

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251328
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461750
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727164
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111932
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
30
Alfa
AF:
0.0000654
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:2
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:1Uncertain:1
Apr 01, 2007
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Sep 04, 2024
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

The p.Glu425Ter variant in DARS2 has been reported in at least 2 individuals, in the compound heterozygous state, with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640, 33977142), and has been identified in 0.0003% (3/1179944) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918211). Although this variant has been seen in the general population in the heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. However, this variant has only been reported in individuals while also in cis with another pathogenic variant, and therefore it is unknown whether it is disease causing in isolation. This variant has also been reported in ClinVar (Variation ID: 1065) and has been interpreted as Pathogenic by OMIM, Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC), and Joint Genome Diagnostic Labs from Nijmegen and Maastricht (Radboudumc and MUMC+). This nonsense variant leads to a premature termination codon at position 425, which is predicted to lead to a truncated or absent protein. Loss of function of the DARS2 gene is an established disease mechanism in autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
34
DANN
Uncertain
0.98
Eigen
Uncertain
0.28
Eigen_PC
Benign
-0.024
FATHMM_MKL
Benign
0.18
N
PhyloP100
1.2
Vest4
0.73
GERP RS
4.8
Mutation Taster
=3/197
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs121918211; hg19: chr1-173819546; API