chr1-173825336-GT-G

Variant names:

• chr1-173825336-GT-G
• NM_018122.5:c.109delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018122.5(DARS2):​c.109delT​(p.Ser37HisfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S37S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DARS2 NM_018122.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.635
• Publications: 0 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 12 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 1-173825336-GT-G is Pathogenic according to our data. Variant chr1-173825336-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3063594.Status of the report is criteria_provided_single_submitter, 1 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.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 of 17	NP_060592.2
	DARS2	NM_001365212.1		c.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 of 16	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 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.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.109delT	p.Ser37HisfsTer26	frameshift	Exon 1 of 16	ENSP00000563415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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
PhyloP100		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr1-173794474;