rs769348060
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.257C>T(p.Pro86Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,050 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
MMUT
NM_000255.4 missense
NM_000255.4 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 9.52
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 6-49459210-G-A is Pathogenic according to our data. Variant chr6-49459210-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553773.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 |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.257C>T | p.Pro86Leu | missense_variant | 2/13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.257C>T | p.Pro86Leu | missense_variant | 2/13 | XP_005249200.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.257C>T | p.Pro86Leu | missense_variant | 2/13 | 1 | NM_000255.4 | ENSP00000274813.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251474Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727248
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 09, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2017 | - - |
MMUT-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 21, 2023 | The MMUT c.257C>T variant is predicted to result in the amino acid substitution p.Pro86Leu. This variant has been reported in the compound heterozygous, presumed compound heterozygous, and homozygous states in individuals with methylmalonic acidemia (Worgan et al. 2006. PubMed ID: 16281286; Patient 31, Chu et al. 2016. PubMed ID: 27233228; Nr. 87, Hörster et al. 2020. PubMed ID: 32754920). The c.257C>T variant was also reported in the homozygous state in two unrelated individuals following newborn screening; however, both patients were asymptomatic (Underhill et al. 2013. PubMed ID: 24330302). This variant was also detected in a study of exome sequencing for inborn errors of metabolism in newborns (Supplemental Table 5, Adhikari et al. 2020. PubMed ID: 32778825). Based on in vitro analysis, the c.257C>T (p.Pro86Leu) variant was reported to result in a mild decrease in enzyme activity relative to control, and it was reported to be a thermolabile substitution (Forny et al. 2014. PubMed ID: 25125334). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-49426923-G-A) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/553773/). This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the MUT protein (p.Pro86Leu). This variant is present in population databases (rs769348060, gnomAD 0.01%). This missense change has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 24330302, 27233228). ClinVar contains an entry for this variant (Variation ID: 553773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Loss of disorder (P = 0.0165);
MVP
MPC
ClinPred
D
GERP RS
gMVP
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