rs786204000

Variant names:

• chr12-57515926-C-A
• rs781249411
• NM_004990.4:c.2398C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_004990.4(MARS1):​c.2398C>A​(p.Pro800Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000205 (30/1461522) while in subpopulation EAS AF= 0.000731 (29/39698). AF 95% confidence interval is 0.000522. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARS1	NM_004990.4	c.2398C>A	p.Pro800Thr	missense_variant	Exon 19 of 21	ENST00000262027.10	NP_004981.2
MARS1	XM_047428851.1	c.1696C>A	p.Pro566Thr	missense_variant	Exon 15 of 17		XP_047284807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARS1	ENST00000262027.10	c.2398C>A	p.Pro800Thr	missense_variant	Exon 19 of 21	1	NM_004990.4	ENSP00000262027.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251198 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

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: 0.0000205 AC: 30 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2U Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

not specified Uncertain:1

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MARS1 c.2398C>A (p.Pro800Thr) results in a non-conservative amino acid change located in the Methionyl-tRNA synthetase, anticodon-binding domain (IPR041872) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 1613750 control chromosomes. c.2398C>A has been reported in the literature in the presumed heterozygous state in multiple individuals affected with clinical features of autosomal dominant Charcot-Marie-Tooth disease axonal type 2U (example, Gillespie_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie-Tooth disease axonal type 2U. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, Cui_2023). The following publications have been ascertained in the context of this evaluation (PMID: 36738734, 31356216). ClinVar contains an entry for this variant (Variation ID: 187857). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.062	T;D
Polyphen		0.87	P;.
Vest4		0.91
MutPred		0.49		Gain of catalytic residue at S799 (P = 0);.;
MVP		0.70
MPC		0.83
ClinPred		0.48	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.59

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

Other links and lift over

dbSNP: rs781249411; hg19: chr12-57909709;