1-173828321-C-G

Position:

• chr1-173828321-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018122.5(DARS2):​c.228-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,370,752 control chromosomes in the GnomAD database, including 3,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1478 hom., cov: 30)
  • Exomes 𝑓: 0.011 (1524 hom.)
• Consequence: DARS2 NM_018122.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001504
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.138

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-173828321-C-G is Benign according to our data. Variant chr1-173828321-C-G is described in ClinVar as [Benign]. Clinvar id is 137070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-173828321-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DARS2	NM_018122.5	c.228-12C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.228-12C>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001352141.1
DARS2	NM_001365213.2	c.228-12C>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.228-12C>G		splice_polypyrimidine_tract_variant, intron_variant			NM_018122.5	ENSP00000497569	P1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11595 AN: 147460 Hom.: 1474 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.00160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.0629

GnomAD3 exomes AF: 0.0219 AC: 5479 AN: 250472 Hom.: 656 AF XY: 0.0165 AC XY: 2240 AN XY: 135512

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.000547

Gnomad SAS exome AF: 0.000852

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0108 AC: 13234 AN: 1223162 Hom.: 1524 Cov.: 30 AF XY: 0.00958 AC XY: 5888 AN XY: 614336

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.000631

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.0000219

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0788 AC: 11632 AN: 147590 Hom.: 1478 Cov.: 30 AF XY: 0.0768 AC XY: 5522 AN XY: 71922

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000212

Gnomad4 SAS AF: 0.00114

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.0623

Alfa AF: 0.00793 Hom.: 15

Bravo AF: 0.0878

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 28097321, 23065766, 27884173, 21427441) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2020	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: BS1,BS2 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.63
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.10
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

Publications

LitVar

Other links and lift over

dbSNP: rs9425753; hg19: chr1-173797459;