12-57490333-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_004990.4(MARS1):c.617C>T(p.Pro206Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000828 in 1,612,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004990.4 missense
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MARS1 | NM_004990.4 | c.617C>T | p.Pro206Leu | missense_variant | Exon 6 of 21 | ENST00000262027.10 | NP_004981.2 | |
MARS1 | XM_047428852.1 | c.617C>T | p.Pro206Leu | missense_variant | Exon 6 of 15 | XP_047284808.1 | ||
MARS1 | XM_047428851.1 | c.-86C>T | 5_prime_UTR_variant | Exon 2 of 17 | XP_047284807.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000611 AC: 93AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000716 AC: 180AN: 251306Hom.: 0 AF XY: 0.000721 AC XY: 98AN XY: 135866
GnomAD4 exome AF: 0.000851 AC: 1243AN: 1460390Hom.: 0 Cov.: 32 AF XY: 0.000826 AC XY: 600AN XY: 726496
GnomAD4 genome AF: 0.000611 AC: 93AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74488
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the MARS protein (p.Pro206Leu). This variant is present in population databases (rs138776588, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease and/or ventricular arrhythmia (PMID: 25913036; internal data). ClinVar contains an entry for this variant (Variation ID: 542171). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
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not provided Benign:2
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not specified Benign:1
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. -
Charcot-Marie-Tooth disease Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at