chr12-57500337-T-C

Variant names:

Variant summary

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

The NM_004990.4(MARS1):c.1108T>C(p.Phe370Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,074 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MARS1
NM_004990.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3O:1

Conservation

PhyloP100: 7.46

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]

MARS1 links:

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, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARS1	NM_004990.4 link	c.1108T>C	p.Phe370Leu	missense_variant	Exon 10 of 21	ENST00000262027.10	NP_004981.2	P56192-1
MARS1	XM_047428851.1 link	c.406T>C	p.Phe136Leu	missense_variant	Exon 6 of 17		XP_047284807.1
MARS1	XM_047428852.1 link	c.1108T>C	p.Phe370Leu	missense_variant	Exon 10 of 15		XP_047284808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARS1	ENST00000262027.10 link	c.1108T>C	p.Phe370Leu	missense_variant	Exon 10 of 21	1	NM_004990.4	ENSP00000262027.5		P56192-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

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:

0.0000318

AC:

AN:

251488

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135918

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:

0.0000615

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727222

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:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Pathogenic:1

Oct 08, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jul 06, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F370L variant in the MARS gene has been reported previously, in trans with another missense variant, in an infant with failure to thrive, interstitial lung and liver disease, intermittent lactic acidosis, aminoaciduria, hypothyroidism, and transfusion-dependent anemia and motor delay. Functional studies showed that F370L significantly reduced the ability of MARS to couple methionine to its cognate tRNA, leading to 18% of wild type activity (vanMeel et al., 2013). The F370L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F370L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. We interpret F370L as a likely pathogenic variant. -

not specified

Uncertain:1

Feb 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F370L variant (also known as c.1108T>C), located in coding exon 10 of the MARS gene, results from a T to C substitution at nucleotide position 1108. The phenylalanine at codon 370 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in one individual suspected of having Charcot-Marie-Tooth disease (Volodarsky M et al. J Med Genet, 2021 Apr;58:284-288). This variant was detected as compound heterozygous finding with another alteration in MARS in one individual whose multi-organ phenotype included lung and liver disease (van Meel E et al. BMC Med Genet, 2013 Oct;14:106). In an in vitro aminoacylation assay, this variant was found to significantly reduce the ability of MARS to couple methionine to its cognate tRNA (van Meel E et al. BMC Med Genet, 2013 Oct;14:106). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Uncertain:1

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Experimental studies have shown that this missense change affects MARS function (PMID: 24103465). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 68463). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 370 of the MARS protein (p.Phe370Leu). This missense change has been observed in individual(s) with clinical features of MARS-related conditions (PMID: 24103465, 32376792). This variant is present in population databases (rs140467171, gnomAD 0.006%). -

MARS-related disorder

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.97

MutPred

0.79

Gain of catalytic residue at F370 (P = 0.0211);

MVP

0.71

MPC

0.96

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over