NM_004539.4:c.1616A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004539.4(NARS1):​c.1616A>G​(p.Tyr539Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 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 0.0000066 ( 0 hom., cov: 33)

Consequence

NARS1
NM_004539.4 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.59
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NARS1NM_004539.4 linkc.1616A>G p.Tyr539Cys missense_variant Exon 14 of 14 ENST00000256854.10 NP_004530.1 O43776-1
NARS1XM_005266700.3 linkc.1613A>G p.Tyr538Cys 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.1616A>G p.Tyr539Cys missense_variant Exon 14 of 14 1 NM_004539.4 ENSP00000256854.4 O43776-1
NARS1ENST00000586807.5 linkn.*796A>G non_coding_transcript_exon_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19
NARS1ENST00000589314.1 linkn.696A>G non_coding_transcript_exon_variant Exon 3 of 3 5
NARS1ENST00000586807.5 linkn.*796A>G 3_prime_UTR_variant Exon 12 of 12 2 ENSP00000464988.1 K7EJ19

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250830
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135718
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:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 12, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1616A>G (p.Y539C) alteration is located in exon 14 (coding exon 14) of the NARS gene. This alteration results from a A to G substitution at nucleotide position 1616, causing the tyrosine (Y) at amino acid position 539 to be replaced by a cysteine (C). 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
0.94
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-8.5
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.83
Loss of catalytic residue at Y539 (P = 0.0215);
MVP
0.99
MPC
1.1
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.95
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: rs1293325505; hg19: chr18-55268915; API