rs768176676
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_052845.4(MMAB):c.562G>A(p.Val188Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,610,614 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. V188G) has been classified as Pathogenic.
Frequency
Consequence
NM_052845.4 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 |
---|---|---|---|---|---|---|---|
MMAB | NM_052845.4 | c.562G>A | p.Val188Met | missense_variant | 7/9 | ENST00000545712.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMAB | ENST00000545712.7 | c.562G>A | p.Val188Met | missense_variant | 7/9 | 1 | NM_052845.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151914Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249032Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135092
GnomAD4 exome AF: 0.0000261 AC: 38AN: 1458700Hom.: 0 Cov.: 35 AF XY: 0.0000276 AC XY: 20AN XY: 725928
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151914Hom.: 0 Cov.: 30 AF XY: 0.0000539 AC XY: 4AN XY: 74206
ClinVar
Submissions by phenotype
Methylmalonic aciduria, cblB type Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Baumgartner lab, University Children's Hospital Zurich | Jun 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | This variant is present in population databases (rs768176676, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is not expected to disrupt MMAB protein function. ClinVar contains an entry for this variant (Variation ID: 551432). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin B type (PMID: 25760844, 34796408; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 188 of the MMAB protein (p.Val188Met). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at