rs587776889
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.609G>A(p.Trp203Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 stop_gained
NM_015506.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.61
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 14 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. Fraction of 0.283 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45508975-G-A is Pathogenic according to our data. Variant chr1-45508975-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45508975-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.609G>A | p.Trp203Ter | stop_gained | 4/4 | ENST00000401061.9 | NP_056321.2 | |
MMACHC | NM_001330540.2 | c.438G>A | p.Trp146Ter | stop_gained | 4/4 | NP_001317469.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.609G>A | p.Trp203Ter | stop_gained | 4/4 | 2 | NM_015506.3 | ENSP00000383840 | P1 | |
MMACHC | ENST00000616135.1 | c.438G>A | p.Trp146Ter | stop_gained | 4/5 | 2 | ENSP00000478859 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249554Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135394
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727246
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74466
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:15
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University | May 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2017 | Variant summary: The MMACHC c.609G>A (p.Trp203X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121366 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the homozygous and compound heterozygous state, and there is evidence the variant may be a founder mutation in the Chinese population (Lerner-Ellis_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PM3_VeryStrong+PP4+PVS1_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000441, PM2). he variant was observed in trans with a pathogenic variant (NM_015506.2: c.394C>T) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000030800.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | research | Neurology Department, Peking University First Hospital | Apr 23, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Precision Medicine Center, Zhengzhou University | Dec 01, 2023 | PVS1,PM2_p,PM3 - |
Pathogenic, no assertion criteria provided | case-control | Biochemistry Laboratory of CDMU, Chengde Medical University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Trp203*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs587776889, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with MMACHC-related conditions (PMID: 16311595, 20631720, 23954310, 25772322, 27383490, 28327205). ClinVar contains an entry for this variant (Variation ID: 30800). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital | Feb 28, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | Nonsense variant predicted to result in protein truncation, as the last 80 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 26283149, 26149271, 34704411, 33691766, 34474183, 34102818, 35361390, 35085585, 23591356, 22995991, 20631720, 21055272, 26563984, 27383490, 27751223, 29042959, 28327205, 29581464, 29340559, 29068997, 30712249, 29045954, 31178897, 30863077, 30564975, 31574870, 31203424, 31697851, 31965297, 30157807, 32443968, 31998365, 29731766, 32005694, 34539730, 32957924, 32943488, 32901917, 32712949, 32778825, 33473346, 33914258, 34076870, 33982424, 35578252, 35935352, 35709987, 34953813, 33327995, 35193651, 31328266, 35660814, 16311595, 32746869) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 25, 2017 | The p.Trp203Ter variant creates a termination codon in the MMACHC protein at codon 203 in exon 4 which is predicted to result in a truncated or absent protein product. In a cohort of 204 individuals suspected with inborn errors in cobalamin metabolism, the p.Trp203Ter was identified in the MMACHC gene from 7 individuals with pathogenic bi-allelic variants, including 5 homozygotes (Lerner-Ellis et. al. 2006). Furthermore, the p.Trp203Ter was observed in 52 out of 71 Chinese patients, including 15 homozygotes with elevated methylmalonic aciduria (MMA) and homocystinuria (HC), whereby haplotype analysis determined that it may have been caused by a founder effect in this population (Liu et. al. 2010). This variant is reported in ClinVar (Variation ID: 30800) as pathogenic. It is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 246,224 chromosomes). Based on these observations the p.Trp203Ter is pathogenic. - |
Methylmalonic acidemia with homocystinuria cblC Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Disorders of Intracellular Cobalamin Metabolism Other:1
not provided, no classification provided | literature only | GeneReviews | - | Common in people of Chinese ancestry. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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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