rs753793246

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001349.4(DARS1):ā€‹c.1460G>Cā€‹(p.Arg487Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,528 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

DARS1
NM_001349.4 missense

Scores

16
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.69
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-135907363-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DARS1NM_001349.4 linkc.1460G>C p.Arg487Pro missense_variant Exon 16 of 16 ENST00000264161.9 NP_001340.2 P14868-1A0A140VJW5
DARS1NM_001293312.1 linkc.1160G>C p.Arg387Pro 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.1460G>C p.Arg487Pro missense_variant Exon 16 of 16 1 NM_001349.4 ENSP00000264161.4 P14868-1
DARS1ENST00000422708.3 linkc.521G>C p.Arg174Pro missense_variant Exon 6 of 6 2 ENSP00000387508.1 H7BZ35
DARS1ENST00000478212.5 linkn.354G>C non_coding_transcript_exon_variant Exon 3 of 3 2
DARS1ENST00000489964.5 linkn.709G>C non_coding_transcript_exon_variant Exon 5 of 5 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249204
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134914
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:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1452528
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722742
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000381
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.90
Loss of MoRF binding (P = 0.0093);.;
MVP
0.99
MPC
0.86
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.99
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs753793246; hg19: chr2-136664932; API