rs761221416

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_015506.3(MMACHC):​c.566G>A​(p.Arg189His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 missense

Scores

9
8
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:2

Conservation

PhyloP100: 7.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_015506.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45508932-G-A is Pathogenic according to our data. Variant chr1-45508932-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417857.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
MMACHCNM_015506.3 linkuse as main transcriptc.566G>A p.Arg189His missense_variant 4/4 ENST00000401061.9 NP_056321.2
MMACHCNM_001330540.2 linkuse as main transcriptc.395G>A p.Arg132His missense_variant 4/4 NP_001317469.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MMACHCENST00000401061.9 linkuse as main transcriptc.566G>A p.Arg189His missense_variant 4/42 NM_015506.3 ENSP00000383840 P1
MMACHCENST00000616135.1 linkuse as main transcriptc.395G>A p.Arg132His missense_variant 4/52 ENSP00000478859

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000280
AC:
7
AN:
249560
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135392
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cobalamin C disease Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 28, 2023This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 189 of the MMACHC protein (p.Arg189His). This variant is present in population databases (rs761221416, gnomAD 0.02%). This missense change has been observed in individual(s) with MMACHC-related conditions (PMID: 26658511, 32164588). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 417857). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Arg189 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16311595, 18164228, 18245139, 19760748, 24599607, 29294253). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submissionresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaAug 15, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 20, 2024- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 10, 2023Variant summary: MMACHC c.566G>A (p.Arg189His) results in a non-conservative amino acid change in 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 2.8e-05 in 249560 control chromosomes (gnomAD). c.566G>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (Ahrens-Nicklas_2018, Philipponnet_2020, Pajares_2021, Wang_2021). These data indicate that the variant is likely to be associated with disease. Other variants at this amino acid residue have been reported in affected individuals (PMIDs: 31279840, 16311595, 29294253) and are cited as pathogenic in ClinVar. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, flagged submissionclinical testingCounsylJun 02, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.4
D;.
REVEL
Pathogenic
0.75
Sift
Benign
0.095
T;.
Sift4G
Uncertain
0.021
D;D
Polyphen
1.0
D;.
Vest4
0.65
MutPred
0.55
Loss of helix (P = 0.0626);.;
MVP
0.99
MPC
0.077
ClinPred
0.93
D
GERP RS
5.7
Varity_R
0.48
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs761221416; hg19: chr1-45974604; API