Variant chr1-173857643-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_018122.5(DARS2):c.1876C>G(p.Leu626Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L626M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.35

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-173857643-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 1-173857643-C-G is Pathogenic according to our data. Variant chr1-173857643-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1058.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DARS2	NM_018122.5 linkuse as main transcript	c.1876C>G	p.Leu626Val	missense_variant	17/17	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1 linkuse as main transcript	c.1723C>G	p.Leu575Val	missense_variant	16/16		NP_001352141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 linkuse as main transcript	c.1876C>G	p.Leu626Val	missense_variant	17/17		NM_018122.5	ENSP00000497569	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

.;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.8

M;.;.;M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

N;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Benign

0.12

T;.;.;.;.

Sift4G

Uncertain

0.040

D;.;.;.;.

Polyphen

0.95

P;.;.;P;.

Vest4

0.83

MutPred

0.88

Gain of methylation at K627 (P = 0.1216);.;.;Gain of methylation at K627 (P = 0.1216);.;

MVP

0.92

MPC

0.75

ClinPred

0.91

GERP RS

1.2

Varity_R

0.38

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over