1-173828364-G-A

Variant names:

• chr1-173828364-G-A
• rs1209550754
• NM_018122.5:c.259G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_018122.5(DARS2):​c.259G>A​(p.Asp87Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,608,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D87G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 1.45
• Publications: 3 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 1-173828364-G-A is Pathogenic according to our data. Variant chr1-173828364-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434896.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18658161). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	NM_018122.5	MANE Select	c.259G>A	p.Asp87Asn	missense	Exon 3 of 17	NP_060592.2
	DARS2	NM_001365212.1		c.259G>A	p.Asp87Asn	missense	Exon 3 of 16	NP_001352141.1
	DARS2	NM_001365213.2		c.259G>A	p.Asp87Asn	missense	Exon 3 of 14	NP_001352142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.259G>A	p.Asp87Asn	missense	Exon 3 of 17	ENSP00000497569.1
	DARS2	ENST00000647645.1		c.259G>A	p.Asp87Asn	missense	Exon 3 of 16	ENSP00000497450.1
	DARS2	ENST00000648807.1		c.259G>A	p.Asp87Asn	missense	Exon 3 of 16	ENSP00000497472.1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460590 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 726660

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111246

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148096 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71828

African (AFR) AF: 0.00 AC: 0 AN: 40012

American (AMR) AF: 0.00 AC: 0 AN: 14412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00 AC: 0 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67552

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:1 Uncertain:1 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Jan 16, 2025

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.Asp87Asn variant in DARS2 has been reported in 1 individual, in the compound heterozygous state, with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Rathore 2017), and has been identified in 0.002% (2/90868) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1209550754). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 434896) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and GenomeConnect (ClinGen). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Asp87Asn variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting, PM3 (Richards 2015).

Feb 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.021
Sift	Benign	0.054	T
Sift4G	Benign	0.17	T
Polyphen		0.059	B
Vest4		0.15
MutPred		0.42		Loss of stability (P = 0.0723)
MVP		0.40
MPC		0.24
ClinPred		0.59	D
GERP RS		1.7
Varity_R		0.11
gMVP		0.61
Mutation Taster		=95/5	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1209550754; hg19: chr1-173797502;