rs761221416
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.566G>A(p.Arg189His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 missense
NM_015506.3 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 7.61
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_015506.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45508932-G-A is Pathogenic according to our data. Variant chr1-45508932-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417857.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 |
---|---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.566G>A | p.Arg189His | missense_variant | 4/4 | ENST00000401061.9 | NP_056321.2 | |
MMACHC | NM_001330540.2 | c.395G>A | p.Arg132His | missense_variant | 4/4 | NP_001317469.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.566G>A | p.Arg189His | missense_variant | 4/4 | 2 | NM_015506.3 | ENSP00000383840 | P1 | |
MMACHC | ENST00000616135.1 | c.395G>A | p.Arg132His | missense_variant | 4/5 | 2 | ENSP00000478859 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249560Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135392
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727246
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 189 of the MMACHC protein (p.Arg189His). This variant is present in population databases (rs761221416, gnomAD 0.02%). This missense change has been observed in individual(s) with MMACHC-related conditions (PMID: 26658511, 32164588). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 417857). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Arg189 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16311595, 18164228, 18245139, 19760748, 24599607, 29294253). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, flagged submission | research | Division of Human Genetics, Children's Hospital of Philadelphia | Aug 15, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2023 | Variant summary: MMACHC c.566G>A (p.Arg189His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249560 control chromosomes (gnomAD). c.566G>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (Ahrens-Nicklas_2018, Philipponnet_2020, Pajares_2021, Wang_2021). These data indicate that the variant is likely to be associated with disease. Other variants at this amino acid residue have been reported in affected individuals (PMIDs: 31279840, 16311595, 29294253) and are cited as pathogenic in ClinVar. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jun 02, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of helix (P = 0.0626);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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