GeneBe

rs1553162918

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_015506.3(MMACHC):​c.500delC​(p.Pro167GlnfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P167P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.57

Publications

0 publications found
Variant links:
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]
MMACHC Gene-Disease associations (from GenCC):
  • methylmalonic aciduria and homocystinuria type cblC
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45508864-GC-G is Pathogenic according to our data. Variant chr1-45508864-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 553370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMACHCNM_015506.3 linkc.500delC p.Pro167GlnfsTer3 frameshift_variant Exon 4 of 4 ENST00000401061.9 NP_056321.2
MMACHCNM_001330540.2 linkc.329delC p.Pro110GlnfsTer3 frameshift_variant Exon 4 of 4 NP_001317469.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMACHCENST00000401061.9 linkc.500delC p.Pro167GlnfsTer3 frameshift_variant Exon 4 of 4 2 NM_015506.3 ENSP00000383840.4
MMACHCENST00000616135.1 linkc.329delC p.Pro110GlnfsTer3 frameshift_variant Exon 4 of 5 2 ENSP00000478859.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112010
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cobalamin C disease Pathogenic:6
Dec 02, 2019
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 16, 2017
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 11, 2023
Genome-Nilou Lab
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 20, 2021
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 10, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro167Glnfs*3) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acid(s) of the MMACHC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cobalamin C deficiency (PMID: 26658511). ClinVar contains an entry for this variant (Variation ID: 553370). This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Trp203*) have been determined to be pathogenic (PMID: 16311595, 20631720, 23954310, 27383490, 28327205). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Oct 14, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: MMACHC c.500delC (p.Pro167GlnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249506 control chromosomes (gnomAD). c.500delC has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Ahrens-Nicklas_2017, Lerner-Ellis_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
4.6
Mutation Taster
=3/197
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1553162918; hg19: chr1-45974536; API