rs756195708
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_052845.4(MMAB):c.584G>A(p.Arg195His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000131 in 1,608,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R195C) has been classified as Uncertain significance.
Frequency
Consequence
NM_052845.4 missense, splice_region
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.584G>A | p.Arg195His | missense_variant, splice_region_variant | 7/9 | ENST00000545712.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMAB | ENST00000545712.7 | c.584G>A | p.Arg195His | missense_variant, splice_region_variant | 7/9 | 1 | NM_052845.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151578Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000806 AC: 2AN: 248074Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134732
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1456432Hom.: 0 Cov.: 36 AF XY: 0.00000690 AC XY: 5AN XY: 724766
GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151578Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2AN XY: 74004
ClinVar
Submissions by phenotype
Methylmalonic aciduria, cblB type Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 17, 2022 | This sequence change affects codon 195 of the MMAB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MMAB protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs756195708, gnomAD 0.003%). This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20556797). ClinVar contains an entry for this variant (Variation ID: 218322). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 20556797). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2023 | - - |
Methylmalonic acidemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 16, 2018 | Variant summary: MMAB c.584G>A (p.Arg195His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Jorge-Finnigan_2010). The variant was observed with an allele frequency of 8.2e-06 in 243566 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MMAB causing Methylmalonic Acidemia (8.2e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.584G>A, was observed in two siblings, one presenting with Methylmalonic Acidemia, while the sibling with the same genotype was asymptomatic (Jorge-Finnigan_2010). Multiple publications have functionally assessed the variant and observed the variant to affect splicing, but does produce a limited amount of wild type protein (Jorge-Finnigan_2010), along with presenting functional implications on proper MMAB protein function (Brasil_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at