Variant 1-173825286-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018122.5(DARS2):c.57A>C(p.Arg19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0881705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.57A>C	p.Arg19Ser	missense_variant	1/17	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.57A>C	p.Arg19Ser	missense_variant	1/16		NP_001352141.1
DARS2	NM_001365213.2 link	c.57A>C	p.Arg19Ser	missense_variant	1/14		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.57A>C	p.Arg19Ser	missense_variant	1/17		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.039

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

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.53

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

M_CAP

Benign

0.025

MetaRNN

Benign

0.088

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

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

PrimateAI

Benign

0.25

PROVEAN

Benign

0.24

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

REVEL

Benign

0.082

Sift

Benign

0.16

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

Sift4G

Benign

0.60

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

Polyphen

0.0080

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

Vest4

0.21

MutPred

0.42

Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);Gain of glycosylation at R19 (P = 0.0249);

MVP

0.81

MPC

0.29

ClinPred

0.058

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.54

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