Genetic Variant NM_018122.5:c.133A>G (chr1-173826692-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_018122.5(DARS2):c.133A>G(p.Ser45Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.35

Publications

7 publications found

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 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

DARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

PP5

Variant 1-173826692-A-G is Pathogenic according to our data. Variant chr1-173826692-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1063.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.133A>G	p.Ser45Gly	missense_variant	Exon 2 of 17	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.133A>G	p.Ser45Gly	missense_variant	Exon 2 of 16		NP_001352141.1
DARS2	NM_001365213.2 link	c.133A>G	p.Ser45Gly	missense_variant	Exon 2 of 14		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.133A>G	p.Ser45Gly	missense_variant	Exon 2 of 17		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443458

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718032

African (AFR)

AF:

0.00

AC:

AN:

32512

American (AMR)

AF:

0.00

AC:

AN:

42920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

82956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101938

Other (OTH)

AF:

0.00

AC:

AN:

59626

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

Apr 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

T;.;.;.;T;.;.

Eigen

Benign

0.0079

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.70

.;T;T;T;T;T;T

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.7

L;.;.;.;L;.;.

PhyloP100

7.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

N;.;.;.;.;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.034

D;.;.;.;.;.;.

Sift4G

Uncertain

0.014

D;.;.;.;.;.;.

Polyphen

0.10

B;.;.;.;B;.;.

Vest4

0.80

MutPred

0.78

Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);Loss of disorder (P = 0.0757);

MVP

0.87

MPC

0.22

ClinPred

0.79

GERP RS

5.4

Varity_R

0.46

gMVP

0.55

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over