rs113808165

Positions:

• chr12-57515034-G-A
• chr12-57515034-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004990.4(MARS1):​c.2180G>A​(p.Arg727Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,614,178 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R727W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (38 hom.)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008411497).
• BP6: Variant 12-57515034-G-A is Benign according to our data. Variant chr12-57515034-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 380553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57515034-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00454 (692/152290) while in subpopulation NFE AF= 0.00676 (460/68026). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARS1	NM_004990.4	c.2180G>A	p.Arg727Gln	missense_variant	17/21	ENST00000262027.10
MARS1	XM_047428851.1	c.1478G>A	p.Arg493Gln	missense_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10	c.2180G>A	p.Arg727Gln	missense_variant	17/21	1	NM_004990.4	P1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00483 AC: 1215 AN: 251464 Hom.: 4 AF XY: 0.00491 AC XY: 667 AN XY: 135910

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00705

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00616 AC: 8999 AN: 1461888 Hom.: 38 Cov.: 32 AF XY: 0.00596 AC XY: 4338 AN XY: 727244

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74476

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00676

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00534 Hom.: 3

Bravo AF: 0.00378

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00503 AC: 611

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2021	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MARS1: BP4, BS2 -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

MARS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	0.87	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.027
Sift	Benign	0.33	T
Sift4G	Benign	0.41	T
Polyphen		0.0090	B
Vest4		0.36
MVP		0.35
MPC		0.29
ClinPred		0.0088	T
GERP RS		-0.072
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.046
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs113808165; hg19: chr12-57908817; COSMIC: COSV56252750; COSMIC: COSV56252750;