rs117914586

chr12-57512360-A-G

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.1753+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,586,112 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (35 hom.)
• Consequence: MARS1 NM_004990.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003349
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.28

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 (BayesDel_noAF=-0.85).
• BP6: Variant 12-57512360-A-G is Benign according to our data. Variant chr12-57512360-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 374666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57512360-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0042 (639/152260) while in subpopulation NFE AF= 0.00697 (474/68026). AF 95% confidence interval is 0.00645. There are 2 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARS1	NM_004990.4	c.1753+7A>G		splice_region_variant, intron_variant		ENST00000262027.10
MARS1	XM_047428851.1	c.1051+7A>G		splice_region_variant, intron_variant
MARS1	XM_047428852.1	c.*45+7A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10	c.1753+7A>G		splice_region_variant, intron_variant		1	NM_004990.4	P1

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 638 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00437 AC: 1095 AN: 250744 Hom.: 7 AF XY: 0.00442 AC XY: 599 AN XY: 135500

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00780

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00603 AC: 8645 AN: 1433852 Hom.: 35 Cov.: 27 AF XY: 0.00588 AC XY: 4201 AN XY: 714884

Gnomad4 AFR exome AF: 0.000668

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.000347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000409

Gnomad4 FIN exome AF: 0.00321

Gnomad4 NFE exome AF: 0.00732

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74428

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00697

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.00581 Hom.: 1

Bravo AF: 0.00431

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00729

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MARS1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 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. -

Charcot-Marie-Tooth disease Benign:1

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 30, 2024

- -

MARS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2023

This variant is classified as 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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.8
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs117914586; hg19: chr12-57906143;