2-135907342-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM2PM5PP3_Strong

The NM_001349.4(DARS1):​c.1480C>T​(p.Arg494Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000626 in 1,437,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R494G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

DARS1
NM_001349.4 missense

Scores

18
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.55
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_001349.4 (DARS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-135907342-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS1NM_001349.4 linkc.1480C>T p.Arg494Cys missense_variant Exon 16 of 16 ENST00000264161.9 NP_001340.2 P14868-1A0A140VJW5
DARS1NM_001293312.1 linkc.1180C>T p.Arg394Cys missense_variant Exon 15 of 15 NP_001280241.1 P14868-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DARS1ENST00000264161.9 linkc.1480C>T p.Arg494Cys missense_variant Exon 16 of 16 1 NM_001349.4 ENSP00000264161.4 P14868-1
DARS1ENST00000422708.3 linkc.541C>T p.Arg181Cys missense_variant Exon 6 of 6 2 ENSP00000387508.1 H7BZ35
DARS1ENST00000478212.5 linkn.374C>T non_coding_transcript_exon_variant Exon 3 of 3 2
DARS1ENST00000489964.5 linkn.729C>T non_coding_transcript_exon_variant Exon 5 of 5 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000626
AC:
9
AN:
1437432
Hom.:
0
Cov.:
30
AF XY:
0.00000699
AC XY:
5
AN XY:
715368
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000261
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000729
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Aug 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with hypomyelination with brain stem and spinal cord involvement and leg spasticity (PMID: 23643384). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 494 of the DARS protein (p.Arg494Cys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.3
H;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.3
D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.93
MutPred
0.86
Gain of catalytic residue at P493 (P = 0.0074);.;
MVP
0.96
MPC
0.83
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.98
gMVP
0.97

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.

Other links and lift over

dbSNP: rs147077598; hg19: chr2-136664912; COSMIC: COSV51540840; COSMIC: COSV51540840; API