rs139600659

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2PM5BP4_ModerateBP6

The NM_004990.4(MARS1):c.1813G>A(p.Asp605Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D605V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 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 U:1B:1

Conservation

PhyloP100: 9.41

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-57512811-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 189365.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.15857759).

BP6

Variant 12-57512810-G-A is Benign according to our data. Variant chr12-57512810-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MARS1	NM_004990.4 linkuse as main transcript	c.1813G>A	p.Asp605Asn	missense_variant	15/21	ENST00000262027.10
MARS1	XM_047428851.1 linkuse as main transcript	c.1111G>A	p.Asp371Asn	missense_variant	11/17
MARS1	XM_047428852.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10 linkuse as main transcript	c.1813G>A	p.Asp605Asn	missense_variant	15/21	1	NM_004990.4	P1	P56192-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00115

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:

0.000956

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251414

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000595

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:

0.0000287

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000849

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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 submitter

clinical testing

Invitae

Jul 31, 2023

ClinVar contains an entry for this variant (Variation ID: 568199). This variant has not been reported in the literature in individuals affected with MARS-related conditions. This variant is present in population databases (rs139600659, gnomAD 0.05%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 605 of the MARS protein (p.Asp605Asn). 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 specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.42

Cadd

Uncertain

Dann

Benign

0.93

DEOGEN2

Benign

0.39

Eigen

Benign

-0.027

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.031

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.22

REVEL

Benign

0.20

Sift

Benign

0.82

Sift4G

Benign

0.91

Polyphen

0.091

Vest4

0.89

MVP

0.38

MPC

0.30

ClinPred

0.18

GERP RS

5.4

Varity_R

0.45

gMVP

0.64

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.

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