rs556977618
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.276G>A(p.Glu92=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000248 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 splice_region, synonymous
NM_015506.3 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9993
2
Clinical Significance
Conservation
PhyloP100: 6.33
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45507550-G-A is Pathogenic according to our data. Variant chr1-45507550-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161118.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.276G>A | p.Glu92= | splice_region_variant, synonymous_variant | 2/4 | ENST00000401061.9 | NP_056321.2 | |
MMACHC | NM_001330540.2 | c.105G>A | p.Glu35= | splice_region_variant, synonymous_variant | 2/4 | NP_001317469.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.276G>A | p.Glu92= | splice_region_variant, synonymous_variant | 2/4 | 2 | NM_015506.3 | ENSP00000383840 | P1 | |
MMACHC | ENST00000616135.1 | c.105G>A | p.Glu35= | splice_region_variant, synonymous_variant | 2/5 | 2 | ENSP00000478859 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change affects codon 92 of the MMACHC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MMACHC protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with MMACHC-related conditions (PMID: 23837176). ClinVar contains an entry for this variant (Variation ID: 161118). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.276G nucleotide in the MMACHC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 20652818, 23837176, 25894566). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at