rs147370143
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_015702.3(MMADHC):c.578T>C(p.Val193Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,604,280 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0017 ( 3 hom. )
Consequence
MMADHC
NM_015702.3 missense
NM_015702.3 missense
Scores
1
12
5
Clinical Significance
Conservation
PhyloP100: 8.52
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 Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.083274096).
BP6
?
Variant 2-149575742-A-G is Benign according to our data. Variant chr2-149575742-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285847.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00115 (175/152320) while in subpopulation NFE AF= 0.00198 (135/68020). AF 95% confidence interval is 0.00171. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMADHC | NM_015702.3 | c.578T>C | p.Val193Ala | missense_variant | 6/8 | ENST00000303319.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMADHC | ENST00000303319.10 | c.578T>C | p.Val193Ala | missense_variant | 6/8 | 1 | NM_015702.3 | P1 | |
MMADHC | ENST00000422782.2 | c.578T>C | p.Val193Ala | missense_variant | 6/9 | 5 | |||
MMADHC | ENST00000428879.5 | c.578T>C | p.Val193Ala | missense_variant | 5/7 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00115 AC: 175AN: 152202Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00178 AC: 435AN: 244924Hom.: 1 AF XY: 0.00190 AC XY: 251AN XY: 132260
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GnomAD4 exome AF: 0.00174 AC: 2528AN: 1451960Hom.: 3 Cov.: 29 AF XY: 0.00174 AC XY: 1254AN XY: 722192
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GnomAD4 genome ? AF: 0.00115 AC: 175AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Methylmalonic aciduria and homocystinuria type cblD Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 14, 2020 | - - |
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 14, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 16, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2020 | - - |
MMADHC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 01, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Disorders of Intracellular Cobalamin Metabolism Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
P;P;P
Vest4
MVP
MPC
0.058
ClinPred
T
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