chr12-109561076-T-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_052845.4(MMAB):c.548A>T(p.His183Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,541,046 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000093 ( 0 hom. )
Consequence
MMAB
NM_052845.4 missense
NM_052845.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 5.74
Genes affected
MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 12-109561076-T-A is Pathogenic according to our data. Variant chr12-109561076-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218328.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMAB | NM_052845.4 | c.548A>T | p.His183Leu | missense_variant | 7/9 | ENST00000545712.7 | NP_443077.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMAB | ENST00000545712.7 | c.548A>T | p.His183Leu | missense_variant | 7/9 | 1 | NM_052845.4 | ENSP00000445920.1 |
Frequencies
GnomAD3 genomes AF: 0.0000204 AC: 3AN: 147208Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249390Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135188
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GnomAD4 exome AF: 0.00000933 AC: 13AN: 1393838Hom.: 0 Cov.: 35 AF XY: 0.0000115 AC XY: 8AN XY: 692802
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GnomAD4 genome AF: 0.0000204 AC: 3AN: 147208Hom.: 0 Cov.: 30 AF XY: 0.0000140 AC XY: 1AN XY: 71600
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Methylmalonic aciduria, cblB type Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 183 of the MMAB protein (p.His183Leu). This variant is present in population databases (rs752866643, gnomAD 0.009%). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin B type (PMID: 24813872, 30041674). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218328). 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 MMAB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MMAB function (PMID: 24813872). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 07, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2021 | Variant summary: MMAB c.548A>T (p.His183Leu) results in a non-conservative amino acid change located in the Cobalamin adenosyltransferase-like domain (IPR016030) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249390 control chromosomes. c.548A>T has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Methylmalonic Acidemia, cblB type (example. Brasil_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a destabilizing effect and a mild reduction of adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR) activity and half-life (Brasil_2015). Two clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=2 including OMIM as P; VUS. n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of helix (P = 0.0496);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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