rs773488177

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001349.4(DARS1):c.1493G>A(p.Arg498Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000703 in 1,563,788 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

DARS1
NM_001349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.69

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4 link	c.1493G>A	p.Arg498Gln	missense_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2	P14868-1A0A140VJW5
DARS1	NM_001293312.1 link	c.1193G>A	p.Arg398Gln	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.1493G>A	p.Arg498Gln	missense_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4	P14868-1
DARS1	ENST00000422708.3 link	c.554G>A	p.Arg185Gln	missense_variant	Exon 6 of 6	2		ENSP00000387508.1	H7BZ35
DARS1	ENST00000478212.5 link	n.387G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5 link	n.742G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

143374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

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:

0.000220

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248726

AF XY:

0.00000742

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000493

AC:

AN:

1420414

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

706564

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31962

American (AMR)

AF:

0.00

AC:

AN:

43192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23180

East Asian (EAS)

AF:

0.00

AC:

AN:

37006

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

1086492

Other (OTH)

AF:

0.0000175

AC:

AN:

57184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000279

AC:

AN:

143374

Hom.:

Cov.:

AF XY:

0.0000434

AC XY:

AN XY:

69102

show subpopulations

African (AFR)

AF:

0.0000261

AC:

AN:

38346

American (AMR)

AF:

0.00

AC:

AN:

13278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4788

South Asian (SAS)

AF:

0.00

AC:

AN:

4474

European-Finnish (FIN)

AF:

0.000220

AC:

AN:

9104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66878

Other (OTH)

AF:

0.00

AC:

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Uncertain:1

Aug 08, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Inborn genetic diseases

Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1493G>A (p.R498Q) alteration is located in exon 16 (coding exon 16) of the DARS gene. This alteration results from a G to A substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.71

MutPred

0.68

Loss of MoRF binding (P = 0.0421);.;

MVP

0.86

MPC

0.76

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.68

gMVP

0.96

Mutation Taster

=4/96

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs773488177

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