rs121918209

chr1-173826692-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_018122.5(DARS2):c.133A>G(p.Ser45Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 1-173826692-A-G is Pathogenic according to our data. Variant chr1-173826692-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1063.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-173826692-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS2	NM_018122.5	c.133A>G	p.Ser45Gly	missense_variant	2/17	ENST00000649689.2
DARS2	NM_001365212.1	c.133A>G	p.Ser45Gly	missense_variant	2/16
DARS2	NM_001365213.2	c.133A>G	p.Ser45Gly	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS2	ENST00000649689.2	c.133A>G	p.Ser45Gly	missense_variant	2/17		NM_018122.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443458 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;.;.;T;.;.
Eigen	Benign	0.0079
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	L;.;.;.;L;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;.;.;.;.;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.034	D;.;.;.;.;.;.
Sift4G	Uncertain	0.014	D;.;.;.;.;.;.
Polyphen		0.10	B;.;.;.;B;.;.
Vest4		0.80
MutPred		0.78		Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);
MVP		0.87
MPC		0.22
ClinPred		0.79	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs121918209; hg19: chr1-173795830;