1-45508330-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_015506.3(MMACHC):​c.395G>T​(p.Arg132Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MMACHC
NM_015506.3 missense

Scores

9
7
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63
Variant links:
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 51 pathogenic changes around while only 14 benign (78%) in NM_015506.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMACHCNM_015506.3 linkc.395G>T p.Arg132Leu missense_variant Exon 3 of 4 ENST00000401061.9 NP_056321.2 Q9Y4U1
MMACHCNM_001330540.2 linkc.224G>T p.Arg75Leu missense_variant Exon 3 of 4 NP_001317469.1 Q9Y4U1A0A0C4DGU2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMACHCENST00000401061.9 linkc.395G>T p.Arg132Leu missense_variant Exon 3 of 4 2 NM_015506.3 ENSP00000383840.4 Q9Y4U1
MMACHCENST00000616135.1 linkc.224G>T p.Arg75Leu missense_variant Exon 3 of 5 2 ENSP00000478859.1 A0A0C4DGU2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-4.5
D;.
REVEL
Pathogenic
0.69
Sift
Benign
0.14
T;.
Sift4G
Uncertain
0.053
T;T
Polyphen
1.0
D;.
Vest4
0.70
MutPred
0.33
Loss of disorder (P = 0.0674);.;
MVP
0.96
MPC
0.060
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.63
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369335868; hg19: chr1-45974002; API