NM_018122.5:c.259G>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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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

Sel.	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	A0A3B3IT01
	DARS2	NM_001365213.2		c.259G>A	p.Asp87Asn	missense	Exon 3 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.259G>A	p.Asp87Asn	missense	Exon 3 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.259G>A	p.Asp87Asn	missense	Exon 3 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.259G>A	p.Asp87Asn	missense	Exon 3 of 16	ENSP00000563415.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (3)

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;