rs121918209

Variant names:

• chr1-173826692-A-G
• rs121918209
• NM_018122.5:c.133A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 7 publications found

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 1063.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	NM_018122.5	MANE Select	c.133A>G	p.Ser45Gly	missense	Exon 2 of 17	NP_060592.2
	DARS2	NM_001365212.1		c.133A>G	p.Ser45Gly	missense	Exon 2 of 16	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.133A>G	p.Ser45Gly	missense	Exon 2 of 14	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.133A>G	p.Ser45Gly	missense	Exon 2 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.133A>G	p.Ser45Gly	missense	Exon 2 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.133A>G	p.Ser45Gly	missense	Exon 2 of 16	ENSP00000563415.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32512

American (AMR) AF: 0.00 AC: 0 AN: 42920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 82956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101938

Other (OTH) AF: 0.00 AC: 0 AN: 59626

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.0079
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.3
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
Vest4		0.80
MutPred		0.78		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
Mutation Taster		=19/81	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

Other links and lift over

dbSNP: rs121918209; hg19: chr1-173795830;