rs746274670
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.277C>T(p.Arg93Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
MMUT
NM_000255.4 missense
NM_000255.4 missense
Scores
15
1
1
Clinical Significance
Conservation
PhyloP100: 3.95
Genes affected
MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 6-49459190-G-A is Pathogenic according to our data. Variant chr6-49459190-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.277C>T | p.Arg93Cys | missense_variant | 2/13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.277C>T | p.Arg93Cys | missense_variant | 2/13 | XP_005249200.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.277C>T | p.Arg93Cys | missense_variant | 2/13 | 1 | NM_000255.4 | ENSP00000274813.3 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251452Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135906
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727246
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74340
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 93 of the MUT protein (p.Arg93Cys). This variant is present in population databases (rs746274670, gnomAD 0.007%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 26270765, 36717752). ClinVar contains an entry for this variant (Variation ID: 553695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. This variant disrupts the p.Arg93 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1670635, 16281286, 16490061). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, | - | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Sep 12, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
gMVP
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