12-57516258-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004990.4(MARS1):​c.2477C>T​(p.Pro826Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

MARS1
NM_004990.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.28
Variant links:
Genes affected
MARS1 (HGNC:6898): (methionyl-tRNA synthetase 1) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08076632).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MARS1NM_004990.4 linkuse as main transcriptc.2477C>T p.Pro826Leu missense_variant 20/21 ENST00000262027.10 NP_004981.2
MARS1XM_047428851.1 linkuse as main transcriptc.1775C>T p.Pro592Leu missense_variant 16/17 XP_047284807.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MARS1ENST00000262027.10 linkuse as main transcriptc.2477C>T p.Pro826Leu missense_variant 20/211 NM_004990.4 ENSP00000262027 P1P56192-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251478
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135914
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:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000835
AC:
122
AN:
1461872
Hom.:
0
Cov.:
32
AF XY:
0.0000798
AC XY:
58
AN XY:
727240
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:
0.00
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 09, 2022The p.P826L variant (also known as c.2477C>T), located in coding exon 20 of the MARS gene, results from a C to T substitution at nucleotide position 2477. The proline at codon 826 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 826 of the MARS protein (p.Pro826Leu). This variant is present in population databases (rs138343927, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 570331). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
12
DANN
Benign
0.62
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.081
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.63
N;N
REVEL
Benign
0.071
Sift
Benign
0.20
T;T
Sift4G
Benign
0.20
T;T
Polyphen
0.017
B;.
Vest4
0.25
MVP
0.36
MPC
0.25
ClinPred
0.077
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.068
gMVP
0.23

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: rs138343927; hg19: chr12-57910041; COSMIC: COSV56258443; COSMIC: COSV56258443; API