rs397509363
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015702.3(MMADHC):c.419dupA(p.Tyr140fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MMADHC
NM_015702.3 frameshift, stop_gained
NM_015702.3 frameshift, stop_gained
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.25
Genes affected
MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-149576495-G-GT is Pathogenic according to our data. Variant chr2-149576495-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 768.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 |
|---|---|---|---|---|---|---|---|---|
| MMADHC | NM_015702.3 | c.419dupA | p.Tyr140fs | frameshift_variant, stop_gained | 5/8 | ENST00000303319.10 | NP_056517.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MMADHC | ENST00000303319.10 | c.419dupA | p.Tyr140fs | frameshift_variant, stop_gained | 5/8 | 1 | NM_015702.3 | ENSP00000301920.5 | ||
| MMADHC | ENST00000422782.2 | c.419dupA | p.Tyr140fs | frameshift_variant, stop_gained | 5/9 | 5 | ENSP00000408331.2 | |||
| MMADHC | ENST00000428879.5 | c.419dupA | p.Tyr140fs | frameshift_variant, stop_gained | 4/7 | 2 | ENSP00000389060.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251336Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135842
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000342 AC: 5AN: 1461402Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727026
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GnomAD4 genome 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria and homocystinuria type cblD Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 03, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 03, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 04, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 22, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 768). This premature translational stop signal has been observed in individual(s) with MMADHC-related conditions (PMID: 18385497). This variant is present in population databases (rs397509363, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Tyr140*) in the MMADHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMADHC are known to be pathogenic (PMID: 18385497). - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at