rs749936057
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_052845.4(MMAB):c.398C>T(p.Ser133Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_052845.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000165 AC: 4AN: 241942Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131286
GnomAD4 exome AF: 0.00000892 AC: 13AN: 1457742Hom.: 0 Cov.: 32 AF XY: 0.00000828 AC XY: 6AN XY: 724790
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Methylmalonic aciduria, cblB type Pathogenic:2Uncertain:3
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75; 3Cnet: 0.68). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -
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This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 133 of the MMAB protein (p.Ser133Phe). This variant is present in population databases (rs749936057, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of cobalamin B deficiency (PMID: 23707710). 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: 553274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at