rs781249411

chr12-57515926-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57515926-C-A is Pathogenic according to our data. Variant chr12-57515926-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 187857.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-57515926-C-A is described in Lovd as [Likely_pathogenic].
• 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/exons	MANE	UniProt
MARS1	NM_004990.4	c.2398C>A	p.Pro800Thr	missense_variant	19/21	ENST00000262027.10
MARS1	XM_047428851.1	c.1696C>A	p.Pro566Thr	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10	c.2398C>A	p.Pro800Thr	missense_variant	19/21	1	NM_004990.4	P1

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2014

- -

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;.
MutationTaster	Benign	1.0	D;D
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;