rs149660059

Variant names:

• chr1-173853873-C-A
• rs149660059
• NM_018122.5:c.1642C>A
• DARS2 p.Leu548Met

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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
• Publications: 8 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]

GAS5 (HGNC:16355): (growth arrest specific 5) This gene produces a spliced long non-coding RNA and is a member of the 5' terminal oligo-pyrimidine class of genes. It is a small nucleolar RNA host gene, containing multiple C/D box snoRNA genes in its introns. Part of the secondary RNA structure of the encoded transcript mimics glucocorticoid response element (GRE) which means it can bind to the DNA binding domain of the glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1). This action blocks the glucocorticoid receptor from being activated and thereby stops it from regulating the transcription of its target genes. This transcript is also thought to regulate the transcriptional activity of other receptors, such as androgen, progesterone and mineralocorticoid receptors, that can bind to its GRE mimic region. Multiple functions have been associated with this transcript, including cellular growth arrest and apoptosis. It has also been identified as a potential tumor suppressor, with its down-regulation associated with cancer in multiple different tissues. [provided by RefSeq, Mar 2015]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.1642C>A	p.Leu548Met	missense	Exon 15 of 17	NP_060592.2
	DARS2	NM_001365212.1		c.1489C>A	p.Leu497Met	missense	Exon 14 of 16	NP_001352141.1	A0A3B3IT01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.1642C>A	p.Leu548Met	missense	Exon 15 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.1579C>A	p.Leu527Met	missense	Exon 14 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.1546C>A	p.Leu516Met	missense	Exon 14 of 16	ENSP00000563415.1

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

GnomAD2 exomes AF: 0.00440 AC: 1106 AN: 251410 AF XY: 0.00458

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86254

European-Finnish (FIN) AF: 0.0215 AC: 1148 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00295 AC: 3278 AN: 1111966

Other (OTH) AF: 0.00288 AC: 174 AN: 60392

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

African (AFR) AF: 0.000673 AC: 28 AN: 41574

American (AMR) AF: 0.00255 AC: 39 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (3)
-	-	1	DARS2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.63	N
PhyloP100		3.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.48
Sift	Benign	0.21	T
Sift4G	Benign	0.19	T
Varity_R		0.32
gMVP		0.52
Mutation Taster		=98/2	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149660059;

hg19: chr1-173823011;

COSMIC: COSV53405986;

COSMIC: COSV53405986;