18-57601773-C-A

Variant summary

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

The NM_004539.4(NARS1):​c.1526G>T​(p.Gly509Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

NARS1
NM_004539.4 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.78
Variant links:
Genes affected
NARS1 (HGNC:7643): (asparaginyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Asparaginyl-tRNA synthetase is localized to the cytoplasm and belongs to the class II family of tRNA synthetases. The N-terminal domain represents the signature sequence for the eukaryotic asparaginyl-tRNA synthetases. [provided by RefSeq, Jul 2008]

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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 chr18-57601774-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NARS1NM_004539.4 linkc.1526G>T p.Gly509Val missense_variant Exon 14 of 14 ENST00000256854.10 NP_004530.1 O43776-1
NARS1XM_005266700.3 linkc.1523G>T p.Gly508Val missense_variant Exon 14 of 14 XP_005266757.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NARS1ENST00000256854.10 linkc.1526G>T p.Gly509Val missense_variant Exon 14 of 14 1 NM_004539.4 ENSP00000256854.4 O43776-1
NARS1ENST00000586807.5 linkn.*706G>T non_coding_transcript_exon_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19
NARS1ENST00000589314.1 linkn.606G>T non_coding_transcript_exon_variant Exon 3 of 3 5
NARS1ENST00000586807.5 linkn.*706G>T 3_prime_UTR_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jun 13, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.8
H
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-8.6
D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.87
MutPred
0.96
Loss of disorder (P = 0.0345);
MVP
0.99
MPC
1.1
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-55269005; API