rs140573721
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_004990.4(MARS1):āc.2391A>Cā(p.Thr797=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,611,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004990.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MARS1 | NM_004990.4 | c.2391A>C | p.Thr797= | splice_region_variant, synonymous_variant | 18/21 | ENST00000262027.10 | |
MARS1 | XM_047428851.1 | c.1689A>C | p.Thr563= | splice_region_variant, synonymous_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MARS1 | ENST00000262027.10 | c.2391A>C | p.Thr797= | splice_region_variant, synonymous_variant | 18/21 | 1 | NM_004990.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000690 AC: 105AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000776 AC: 193AN: 248650Hom.: 0 AF XY: 0.000810 AC XY: 109AN XY: 134566
GnomAD4 exome AF: 0.000817 AC: 1193AN: 1459564Hom.: 1 Cov.: 32 AF XY: 0.000870 AC XY: 632AN XY: 726102
GnomAD4 genome ? AF: 0.000702 AC: 107AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52AN XY: 74502
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2017 | 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 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 | Jan 31, 2024 | This sequence change affects codon 797 of the MARS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MARS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs140573721, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 389593). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Charcot-Marie-Tooth disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
MARS1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 31, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at