rs765373403
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000255.4(MMUT):βc.1038_1040delβ(p.Leu347del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 31)
Exomes π: 0.0000041 ( 0 hom. )
Consequence
MMUT
NM_000255.4 inframe_deletion
NM_000255.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.95
Genes affected
MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_000255.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
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Variant 6-49453627-TAGA-T is Pathogenic according to our data. Variant chr6-49453627-TAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.1038_1040del | p.Leu347del | inframe_deletion | 5/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.1038_1040del | p.Leu347del | inframe_deletion | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.1038_1040del | p.Leu347del | inframe_deletion | 5/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251228Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135792
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460784Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 726770
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 02, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 19, 2018 | - - |
Pathogenic, no assertion criteria provided | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | May 05, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This variant, c.1038_1040del, results in the deletion of 1 amino acid(s) of the MUT protein (p.Leu347del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765373403, gnomAD 0.006%). This variant has been observed in individual(s) with methylmalonic acidemia (PMID: 15643616, 15781192, 16281286, 26790480). This variant is also known as c.1036-1038delCTT, p.L346del. ClinVar contains an entry for this variant (Variation ID: 225184). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 20, 2021 | - - |
Computational scores
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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