1-32775994-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003680.4(YARS1):​c.1574G>A​(p.Gly525Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,790 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: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

YARS1
NM_003680.4 missense

Scores

5
8
6

Clinical Significance

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

Conservation

PhyloP100: 4.62
Variant links:
Genes affected
YARS1 (HGNC:12840): (tyrosyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
YARS1NM_003680.4 linkuse as main transcriptc.1574G>A p.Gly525Glu missense_variant 13/13 ENST00000373477.9 NP_003671.1
YARS1XM_011542347.3 linkuse as main transcriptc.944G>A p.Gly315Glu missense_variant 11/11 XP_011540649.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
YARS1ENST00000373477.9 linkuse as main transcriptc.1574G>A p.Gly525Glu missense_variant 13/131 NM_003680.4 ENSP00000362576 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250886
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461790
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000187
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 05, 2020The p.G525E variant (also known as c.1574G>A), located in coding exon 13 of the YARS gene, results from a G to A substitution at nucleotide position 1574. The glycine at codon 525 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease dominant intermediate C Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 07, 2023This sequence change replaces glycine with glutamic acid at codon 525 of the YARS protein (p.Gly525Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs774982567, gnomAD 0.007%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 860911). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt YARS protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Uncertain
0.083
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Uncertain
-0.042
T
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.62
N
REVEL
Uncertain
0.40
Sift
Benign
0.068
T
Sift4G
Benign
0.071
T
Polyphen
0.99
D
Vest4
0.75
MutPred
0.40
Gain of sheet (P = 0.0166);
MVP
0.94
MPC
1.2
ClinPred
0.90
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.56
gMVP
0.78

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: rs774982567; hg19: chr1-33241595; COSMIC: COSV105132289; COSMIC: COSV105132289; API