Genetic Variant DARS1:p.Arg494Gly (chr2-135907342-G-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001349.4(DARS1):c.1480C>G(p.Arg494Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000573 in 1,587,118 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R494C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

DARS1
NM_001349.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.55

Publications

3 publications found

Variant links:

Genes affected

DARS1 (HGNC:2678): (aspartyl-tRNA synthetase 1) This gene encodes a member of a multienzyme complex that functions in mediating the attachment of amino acids to their cognate tRNAs. The encoded protein ligates L-aspartate to tRNA(Asp). Mutations in this gene have been found in patients showing hypomyelination with brainstem and spinal cord involvement and leg spasticity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DARS1 Gene-Disease associations (from GenCC):

hypomyelination with brain stem and spinal cord involvement and leg spasticity
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

DARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-135907341-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522693.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.74697 (below the threshold of 3.09). Trascript score misZ: 0.93713 (below the threshold of 3.09). GenCC associations: The gene is linked to hypomyelination with brain stem and spinal cord involvement and leg spasticity.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 2-135907342-G-C is Pathogenic according to our data. Variant chr2-135907342-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 50991.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349.4. 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
	DARS1	NM_001349.4	MANE Select	c.1480C>G	p.Arg494Gly	missense	Exon 16 of 16	NP_001340.2
	DARS1	NM_001293312.1		c.1180C>G	p.Arg394Gly	missense	Exon 15 of 15	NP_001280241.1	P14868-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DARS1	ENST00000264161.9	TSL:1 MANE Select	c.1480C>G	p.Arg494Gly	missense	Exon 16 of 16	ENSP00000264161.4	P14868-1
DARS1	ENST00000952144.1		c.1474C>G	p.Arg492Gly	missense	Exon 16 of 16	ENSP00000622203.1
DARS1	ENST00000952145.1		c.1468C>G	p.Arg490Gly	missense	Exon 16 of 16	ENSP00000622204.1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

149686

Hom.:

Cov.:

show subpopulations

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:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249442

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000612

AC:

AN:

1437432

Hom.:

Cov.:

AF XY:

0.0000615

AC XY:

AN XY:

715368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32492

American (AMR)

AF:

0.00

AC:

AN:

43920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24728

East Asian (EAS)

AF:

0.00

AC:

AN:

38250

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.0000784

AC:

AN:

1097002

Other (OTH)

AF:

0.0000171

AC:

AN:

58630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149686

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

72946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40444

American (AMR)

AF:

0.00

AC:

AN:

14772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67746

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000312

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

PhyloP100

6.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MVP

0.96

MPC

0.81

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.98

Mutation Taster

=1/99

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over