1-45508316-TTAC-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_015506.3(MMACHC):c.388_390delTAC(p.Tyr130del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000396 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_015506.3 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.388_390delTAC | p.Tyr130del | conservative_inframe_deletion | Exon 3 of 4 | ENST00000401061.9 | NP_056321.2 | |
MMACHC | NM_001330540.2 | c.217_219delTAC | p.Tyr73del | conservative_inframe_deletion | Exon 3 of 4 | NP_001317469.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.388_390delTAC | p.Tyr130del | conservative_inframe_deletion | Exon 3 of 4 | 2 | NM_015506.3 | ENSP00000383840.4 | ||
MMACHC | ENST00000616135.1 | c.217_219delTAC | p.Tyr73del | conservative_inframe_deletion | Exon 3 of 5 | 2 | ENSP00000478859.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249426Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135326
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461892Hom.: 0 AF XY: 0.0000481 AC XY: 35AN XY: 727248
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74472
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:7
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Variant summary: MMACHC c.388_390delTAC (p.Tyr130del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249426 control chromosomes. c.388_390delTAC has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with cobalamin C type Methylmalonic Acidemia With Homocystinuria (example, Bourque_2021, Lerner-Ellis_2006, Gizicki_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Tyr130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771707283, gnomAD 0.004%). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria due to cobalamin C deficiency (PMID: 16311595, 24126030; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203833). For these reasons, this variant has been classified as Pathogenic. -
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MMACHC-related disorder Pathogenic:1
The MMACHC c.388_390delTAC variant is predicted to result in an in-frame deletion (p.Tyr130del). This variant is a recurrent variant that has been reported in the homozygous state or along with a second pathogenic MMACHC variant in multiple individuals with confirmed methylmalonic aciduria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Gizicki et al. 2013. PubMed ID: 24126030; Bourque et al. 2020. PubMed ID: 33473346). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45973988-TTAC-T). This variant is interpreted as pathogenic. -
not provided Pathogenic:1
The c.388_390delTAC mutation has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006). This mutation causes the deletion of a Tyrosine codon at amino acid position 130, denoted p.Tyr130del. The variant is found in MMA-MET panel(s). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at