18-57601698-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_004539.4(NARS1):​c.1601G>A​(p.Arg534Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,600 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: not found (cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NARS1
NM_004539.4 missense

Scores

14
4
1

Clinical Significance

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

Conservation

PhyloP100: 5.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NARS1NM_004539.4 linkc.1601G>A p.Arg534Gln missense_variant Exon 14 of 14 ENST00000256854.10 NP_004530.1 O43776-1
NARS1XM_005266700.3 linkc.1598G>A p.Arg533Gln 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.1601G>A p.Arg534Gln missense_variant Exon 14 of 14 1 NM_004539.4 ENSP00000256854.4 O43776-1
NARS1ENST00000586807.5 linkn.*781G>A non_coding_transcript_exon_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19
NARS1ENST00000589314.1 linkn.681G>A non_coding_transcript_exon_variant Exon 3 of 3 5
NARS1ENST00000586807.5 linkn.*781G>A 3_prime_UTR_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250258
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135458
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:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000888
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461600
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727142
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1601G>A (p.R534Q) alteration is located in exon 14 (coding exon 14) of the NARS gene. This alteration results from a G to A substitution at nucleotide position 1601, causing the arginine (R) at amino acid position 534 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Sep 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NARS1: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.65
MutPred
0.87
Loss of MoRF binding (P = 0.0292);
MVP
0.97
MPC
1.0
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.76
gMVP
0.93

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: rs201913524; hg19: chr18-55268930; API