4-145655253-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_172250.3(MMAA):c.1076G>A(p.Arg359Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,008 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R359G) has been classified as Uncertain significance.
Frequency
Consequence
NM_172250.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMAA | NM_172250.3 | c.1076G>A | p.Arg359Gln | missense_variant | 7/7 | ENST00000649156.2 | |
MMAA | NM_001375644.1 | c.1076G>A | p.Arg359Gln | missense_variant | 7/7 | ||
MMAA | XM_011531684.4 | c.1076G>A | p.Arg359Gln | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMAA | ENST00000649156.2 | c.1076G>A | p.Arg359Gln | missense_variant | 7/7 | NM_172250.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
Methylmalonic aciduria, cblA type Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters MMAA gene expression (PMID: 28497574). 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 expected to disrupt MMAA protein function. ClinVar contains an entry for this variant (Variation ID: 218979). This missense change has been observed in individuals with cobalamin A type methylmalonic aciduria (PMID: 15523652, 28497574, 33453710). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 359 of the MMAA protein (p.Arg359Gln). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 17, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at