rs149660059

Positions:

• chr1-173853873-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018122.5(DARS2):​c.1642C>A​(p.Leu548Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,140 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (21 hom.)
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.16

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 (MetaRNN=0.014933974).
• BP6: Variant 1-173853873-C-A is Benign according to our data. Variant chr1-173853873-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 137066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00406 (618/152324) while in subpopulation SAS AF= 0.00414 (20/4830). AF 95% confidence interval is 0.00316. There are 4 homozygotes in gnomad4. There are 376 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS2	NM_018122.5	c.1642C>A	p.Leu548Met	missense_variant	15/17	ENST00000649689.2
DARS2	NM_001365212.1	c.1489C>A	p.Leu497Met	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS2	ENST00000649689.2	c.1642C>A	p.Leu548Met	missense_variant	15/17		NM_018122.5	P1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152206 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00440 AC: 1106 AN: 251410 Hom.: 5 AF XY: 0.00458 AC XY: 623 AN XY: 135886

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00341 AC: 4987 AN: 1461816 Hom.: 21 Cov.: 31 AF XY: 0.00347 AC XY: 2526 AN XY: 727206

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152324 Hom.: 4 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74494

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00399 AC: 484

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DARS2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DARS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.63	N;.;.;N;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N;.;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.21	T;.;.;.;.
Sift4G	Benign	0.19	T;.;.;.;.
Polyphen		0.97	D;.;.;D;.
Vest4		0.47
MVP		0.84
MPC		0.43
ClinPred		0.026	T
GERP RS		4.7
Varity_R		0.32
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs149660059; hg19: chr1-173823011; COSMIC: COSV53405986; COSMIC: COSV53405986;