chr12-57498438-GTGGAACACCCTCT-CTC

Position:

• chr12-57498438-GTGGAACACCCTCT-CTC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004990.4(MARS1):​c.906_919delinsCTC​(p.Gln302HisfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARS1 NM_004990.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.44

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57498438-GTGGAACACCCTCT-CTC is Pathogenic according to our data. Variant chr12-57498438-GTGGAACACCCTCT-CTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475434.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARS1	NM_004990.4	c.906_919delinsCTC	p.Gln302HisfsTer8	frameshift_variant	9/21	ENST00000262027.10	NP_004981.2
MARS1	XM_047428851.1	c.204_217delinsCTC	p.Gln68HisfsTer8	frameshift_variant	5/17		XP_047284807.1
MARS1	XM_047428852.1	c.906_919delinsCTC	p.Gln302HisfsTer8	frameshift_variant	9/15		XP_047284808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARS1	ENST00000262027.10	c.906_919delinsCTC	p.Gln302HisfsTer8	frameshift_variant	9/21	1	NM_004990.4	ENSP00000262027	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2021

The c.906_919del14insCTC pathogenic mutation, located in coding exon 9 of the MARS gene, results from the deletion of 14 nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.Q302Hfs*8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function alterations in MARS have been associated with interstitial lung and liver disease, haploinsufficiency for MARS has not been clearly established as a mechanism of disease for axonal Charcot-Marie-Tooth disease, type 2U (CMT2U). Based on the supporting evidence, this variant is expected to be causative of interstitial lung and liver disease when present along with a second pathogenic variant on the other allele; however, its clinical significance for CMT2U is unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with MARS-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Gln302Hisfs*8) in the MARS gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MARS cause disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555166943; hg19: chr12-57892221;