rs777031588
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000255.4(MMUT):c.1084-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
MMUT
NM_000255.4 splice_polypyrimidine_tract, intron
NM_000255.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 0.105
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
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 6-49451724-T-C is Pathogenic according to our data. Variant chr6-49451724-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203845.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.1084-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000274813.4 | |||
MMUT | XM_005249143.4 | c.1084-10A>G | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.1084-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248136Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134414
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461058Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 726854
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74316
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2021 | Published functional studies demonstrate c.1084-10 A>G results in activation of a cryptic splice site, supporting a damaging effect (Forny et al., 2016; Brasil et al., 2018); This variant is associated with the following publications: (PMID: 27167370, 30041674, 23430940, 31622506, 27535533, 27591164) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change falls in intron 5 of the MUT gene. It does not directly change the encoded amino acid sequence of the MUT protein. This variant is present in population databases (rs777031588, gnomAD 0.02%). This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 23430940; 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: 203845). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 18, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 30, 2017 | - - |
Methylmalonic acidemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The c.1084-10A>G variant in MMUT has been reported in 3 compound heterozygote individuals and 1 homozygous individual with methylmalonic aciduria (Liu 2012 PMID: 23430940, Forny 2016 PMID: 27167370, Yu 2021 PMID: 34668645). It has also been identified in 0.02% (1/4828) of South Asian and 0.004% (2/41418) of African chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 203845). Studies have shown that this variant activates a cryptic splice site in intron 5 of the MMUT gene leading to an insertion that would disrupt the protein (Forny 2016 PMID: 27167370, Brasil 2018 PMID: 30041674). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive methylmalonic acidemia. ACMG/AMP Criteria applied: PM3_S, PS3_M. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2022 | Variant summary: MUT c.1084-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes/weakens a 3' acceptor site, and four predict it creates a new cryptic intronic 3' acceptor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing (Forny_2016 and Brasil_2018). The variant allele was found at a frequency of 3.2e-05 in 248136 control chromosomes (gnomAD). c.1084-10A>G has been reported in the literature in the homozygous and compound heterozygous states in multiple individuals affected with Methylmalonic Acidemia (e.g. Liu_2012, Forny_2016, Devi_2017). These data indicate that the variant is very likely to be associated with disease. One publication reports a homozygous patient with less than 10% activity of Methylmalonyl-CoA mutase when compared to reference range (Forny_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 02, 2020 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
DS_AL_spliceai
Position offset: -10
Find out detailed SpliceAI scores and Pangolin per-transcript scores at