rs121918211

Variant names:

• chr1-173850408-G-T
• rs121918211
• NM_018122.5:c.1273G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-173850408-G-T
• chr1-173850408-G-A
• chr1-173850408-G-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

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 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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:3 U:1
• Conservation: PhyloP100: 1.18
• 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: 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

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.1273G>T	p.Glu425*	stop_gained	Exon 13 of 17	NP_060592.2
	DARS2	NM_001365213.2		c.1273G>T	p.Glu425*	stop_gained	Exon 13 of 14	NP_001352142.1	A0A3B3ITS3
	DARS2	NM_001365212.1		c.1192-2941G>T		intron	N/A	NP_001352141.1	A0A3B3IT01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.1273G>T	p.Glu425*	stop_gained	Exon 13 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.1210G>T	p.Glu404*	stop_gained	Exon 12 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.1177G>T	p.Glu393*	stop_gained	Exon 12 of 16	ENSP00000563415.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251328 AF XY: 0.00000736

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

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

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000654 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs121918211; hg19: chr1-173819546;