rs372918203
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_015506.3(MMACHC):c.364C>A(p.His122Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,614,184 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H122Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015506.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.364C>A | p.His122Asn | missense_variant | 3/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.193C>A | p.His65Asn | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.364C>A | p.His122Asn | missense_variant | 3/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.193C>A | p.His65Asn | missense_variant | 3/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249448Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135332
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 727244
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74478
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 122 of the MMACHC protein (p.His122Asn). This variant is present in population databases (rs372918203, gnomAD 0.05%). This missense change has been observed in individual(s) with MMACHC related conditions (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 557293). 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.His122 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26253414, 31574870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2018 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at