rs1555166943
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_004990.4(MARS1):c.906_919delinsCTC(p.Gln302HisfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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
NM_004990.4 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
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 | UniProt |
---|---|---|---|---|---|---|---|
MARS1 | NM_004990.4 | c.906_919delinsCTC | p.Gln302HisfsTer8 | frameshift_variant | 9/21 | ENST00000262027.10 | |
MARS1 | XM_047428851.1 | c.204_217delinsCTC | p.Gln68HisfsTer8 | frameshift_variant | 5/17 | ||
MARS1 | XM_047428852.1 | c.906_919delinsCTC | p.Gln302HisfsTer8 | frameshift_variant | 9/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MARS1 | ENST00000262027.10 | c.906_919delinsCTC | p.Gln302HisfsTer8 | frameshift_variant | 9/21 | 1 | NM_004990.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
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 | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at