rs751236442
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_015506.3(MMACHC):c.82-11_82-8delTTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 splice_region, intron
NM_015506.3 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.06
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45507342-ACTTT-A is Pathogenic according to our data. Variant chr1-45507342-ACTTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438649.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MMACHC | NM_015506.3 | c.82-11_82-8delTTCT | splice_region_variant, intron_variant | ENST00000401061.9 | NP_056321.2 | |||
| MMACHC | NM_001330540.2 | c.-101_-98delTTCT | 5_prime_UTR_variant | 2/4 | NP_001317469.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MMACHC | ENST00000401061.9 | c.82-11_82-8delTTCT | splice_region_variant, intron_variant | 2 | NM_015506.3 | ENSP00000383840.4 | ||||
| MMACHC | ENST00000616135.1 | c.-90-11_-90-8delTTCT | splice_region_variant, intron_variant | 2 | ENSP00000478859.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248764Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135004
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461694Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 727124
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GnomAD4 genome 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74306
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:4Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Apr 20, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 30, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change falls in intron 1 of the MMACHC gene. It does not directly change the encoded amino acid sequence of the MMACHC protein. This variant is present in population databases (rs751236442, gnomAD 0.002%). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 16714133; Invitae). This variant is also known as c.82-9_12delTTTC. ClinVar contains an entry for this variant (Variation ID: 438649). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 45
Find out detailed SpliceAI scores and Pangolin per-transcript scores at