rs864309726
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_172250.3(MMAA):āc.266T>Cā(p.Leu89Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,088 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 (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.0000068 ( 0 hom. )
Consequence
MMAA
NM_172250.3 missense
NM_172250.3 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 7.49
Genes affected
MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause 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
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MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
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Variant 4-145639405-T-C is Pathogenic according to our data. Variant chr4-145639405-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMAA | NM_172250.3 | c.266T>C | p.Leu89Pro | missense_variant | 2/7 | ENST00000649156.2 | |
MMAA | NM_001375644.1 | c.266T>C | p.Leu89Pro | missense_variant | 2/7 | ||
MMAA | XM_011531684.4 | c.266T>C | p.Leu89Pro | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMAA | ENST00000649156.2 | c.266T>C | p.Leu89Pro | missense_variant | 2/7 | NM_172250.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251246Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135852
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727232
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria, cblA type Pathogenic:3Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MMAA function (PMID: 28497574). 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 MMAA protein function. ClinVar contains an entry for this variant (Variation ID: 218971). This missense change has been observed in individuals with cobalamin A type methylmalonic aciduria (PMID: 15523652, 34915869). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 89 of the MMAA protein (p.Leu89Pro). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;.;D;D;D;.
Vest4
0.92, 0.92
MutPred
Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);
MVP
0.95
MPC
0.68
ClinPred
D
GERP RS
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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