rs118204044
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_015702.3(MMADHC):āc.776T>Cā(p.Leu259Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.000021 ( 0 hom. )
Consequence
MMADHC
NM_015702.3 missense
NM_015702.3 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 5.00
Genes affected
MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.919
PP5
?
Variant 2-149570089-A-G is Pathogenic according to our data. Variant chr2-149570089-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 761.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMADHC | NM_015702.3 | c.776T>C | p.Leu259Pro | missense_variant | 8/8 | ENST00000303319.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMADHC | ENST00000303319.10 | c.776T>C | p.Leu259Pro | missense_variant | 8/8 | 1 | NM_015702.3 | P1 | |
MMADHC | ENST00000422782.2 | c.878T>C | p.Leu293Pro | missense_variant | 9/9 | 5 | |||
MMADHC | ENST00000428879.5 | c.776T>C | p.Leu259Pro | missense_variant | 7/7 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251350Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135856
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461536Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727072
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GnomAD4 genome ? Cov.: 33
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33
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Homocystinuria, cblD type, variant 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 03, 2008 | - - |
Methylmalonic aciduria and homocystinuria type cblD Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MVP
MPC
0.30
ClinPred
D
GERP RS
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