12-57490377-G-A

Variant names:

• chr12-57490377-G-A
• rs200334446
• NM_004990.4:c.661G>A
• MARS1 p.Glu221Lys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). BP4_Moderate

The NM_004990.4(MARS1):c.661G>A (p.Glu221Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000416 (AC=671) in the gnomAD database across 1,612,464 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000514. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: MARS1 NM_004990.4 missense, splice_region
• Scores: Splicing: ADA: 0.8977
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.82
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2U

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal recessive spastic paraplegia type 70

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• spastic paraplegia 70, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004990.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MARS1 NM_004990.4	MANE Select	c.661G>A p.Glu221Lys	missensesplice_region	Exon 6 of 21	Prot: NP_004981.2

MARS1 NM_004990.4

MANE Select

HGVSc / HGVSpc.661G>Ap.Glu221Lys

Exon rankExon 6 of 21

missensesplice_region

Prot: NP_004981.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MARS1 ENST00000262027.10	TSL:1MANE Select	c.661G>A p.Glu221Lys	missensesplice_region	Exon 6 of 21	Prot: ENSP00000262027.5 UniProt:
	MARS1 ENST00000948582.1		c.661G>A p.Glu221Lys	missensesplice_region	Exon 6 of 22	Prot: ENSP00000618641.1 UniProt:
	MARS1 ENST00000948584.1		c.661G>A p.Glu221Lys	missensesplice_region	Exon 6 of 22	Prot: ENSP00000618643.1 UniProt:

MARS1 ENST00000262027.10

TSL:1MANE Select

HGVSc / HGVSpc.661G>Ap.Glu221Lys

Exon rankExon 6 of 21

missensesplice_region

Prot: ENSP00000262027.5UniProt: P56192-1

MARS1 ENST00000948582.1

HGVSc / HGVSpc.661G>Ap.Glu221Lys

Exon rankExon 6 of 22

missensesplice_region

Prot: ENSP00000618641.1UniProt: A0ACI8UHF3

MARS1 ENST00000948584.1

HGVSc / HGVSpc.661G>Ap.Glu221Lys

Exon rankExon 6 of 22

missensesplice_region

Prot: ENSP00000618643.1UniProt: A0ACI8UHG3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000158	AC:24	Hom:0	AN:152204	Cov:32
GnomAD2 exomes	AF: 0.000132	AC:33	Hom:	AN:250848	Cov:
GnomAD4 exome	AF: 0.000443	AC:647	Hom:0	AN:1460260	Cov:32
GnomAD4 genome	AF: 0.000158	AC:24	Hom:0	AN:152204	Cov:32
TOPMed (Bravo)	AF: 0.000200	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000384	AC:104	Hom:0	AN:271122	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000387	11	28420	0.000277	8	28844
Epi25(Epilepsy)	0.000215	9	41958	0.000478	32	66884
SCHEMA(Schizophrenia)	0.000164	20	121806	0.000147	28	190568

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (1)
-	1	-	MARS1-related disorder (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Benign	0.013
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	249/51	polymorphism
MutationAssessor	Benign	1.2	L
PhyloP100	Uncertain	4.8
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.046
Sift	Benign	0.46	T
Sift4G	Benign	0.89	T
Varity_R	N/A	0.038
VESM-3B	Benign	-5.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.67
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200334446;

hg19: chr12-57884160;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar