1-45500378-CTA-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_015506.3(MMACHC):c.48_49del(p.Cys17SerfsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
MMACHC
NM_015506.3 frameshift
NM_015506.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.95
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45500378-CTA-C is Pathogenic according to our data. Variant chr1-45500378-CTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 1076553.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.48_49del | p.Cys17SerfsTer16 | frameshift_variant | 1/4 | ENST00000401061.9 | NP_056321.2 | |
MMACHC | NM_001330540.2 | c.-175_-174del | 5_prime_UTR_variant | 1/4 | NP_001317469.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.48_49del | p.Cys17SerfsTer16 | frameshift_variant | 1/4 | 2 | NM_015506.3 | ENSP00000383840 | P1 | |
MMACHC | ENST00000616135.1 | c.-124_-123del | 5_prime_UTR_variant | 1/5 | 2 | ENSP00000478859 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152190
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74488
GnomAD4 genome
AF:
AC:
1
AN:
152308
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74488
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 26, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant has not been reported in the literature in individuals with MMACHC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Cys17Serfs*16) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at