chr2-135907342-G-C

Variant names:

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

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 id 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 id is 50991.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4 link	c.1480C>G	p.Arg494Gly	missense_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2	P14868-1A0A140VJW5
DARS1	NM_001293312.1 link	c.1180C>G	p.Arg394Gly	missense_variant	Exon 15 of 15		NP_001280241.1	P14868-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DARS1	ENST00000264161.9 link	c.1480C>G	p.Arg494Gly	missense_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4	P14868-1
DARS1	ENST00000422708.3 link	c.541C>G	p.Arg181Gly	missense_variant	Exon 6 of 6	2		ENSP00000387508.1	H7BZ35
DARS1	ENST00000478212.5 link	n.374C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5 link	n.729C>G		non_coding_transcript_exon_variant	Exon 5 of 5	2

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

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

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Pathogenic:2

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, loss of function is likely (PMID: 27816769). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been described regarding symptom severity and MRI findings in a family with three affected siblings (Ong et al. 2020). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition [v2 and v3(non-v2)]: 14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated tRNA synthetases class II domain (DECIPHER). (I) 0704 - Other missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. Two alternative changes, p.(Arg494Cys) and p.(Arg494His), have been reported as VUS and likely pathogenic in ClinVar, respectively. Additionally, p.(Arg494Cys) has also been reported in two compound heterozygous siblings with hypomyelination with brain stem and spinal cord involvement and leg spasticity (PMID: 23643384). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a compound heterozygous state with other missense variants in two families with DARS-related features (PMID: 23643384, Ong et al. 2020). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been identified in a compound heterozygous state in two unrelated families with multiple affected siblings (PMID: 23643384, Ong et al. 2020). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 02, 2013

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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

H;.

PhyloP100

6.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

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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chr2-135907342-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over