chr12-57488092-T-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004990.4(MARS1):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000688 in 1,452,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MARS1
NM_004990.4 start_lost
NM_004990.4 start_lost
Scores
4
10
2
Clinical Significance
Conservation
PhyloP100: 4.24
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]
ARHGAP9 (HGNC:14130): (Rho GTPase activating protein 9) This gene encodes a member of the Rho-GAP family of GTPase activating proteins. The protein has substantial GAP activity towards several Rho-family GTPases in vitro, converting them to an inactive GDP-bound state. It is implicated in regulating adhesion of hematopoietic cells to the extracellular matrix. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MARS1 | NM_004990.4 | c.2T>A | p.Met1? | start_lost | 1/21 | ENST00000262027.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MARS1 | ENST00000262027.10 | c.2T>A | p.Met1? | start_lost | 1/21 | 1 | NM_004990.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152078Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251008Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135664
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GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1452502Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 722960
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74272
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
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 | Jul 24, 2023 | This sequence change affects the initiator methionine of the MARS mRNA. The next in-frame methionine is located at codon 235. This variant is present in population databases (rs760194380, gnomAD 0.002%). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1681667). This variant has not been reported in the literature in individuals affected with MARS-related conditions. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Uncertain
D;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at