rs140356252
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_172250.3(MMAA):c.650T>A(p.Leu217Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L217L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_172250.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMAA | NM_172250.3 | c.650T>A | p.Leu217Ter | stop_gained | 4/7 | ENST00000649156.2 | |
MMAA | NM_001375644.1 | c.650T>A | p.Leu217Ter | stop_gained | 4/7 | ||
MMAA | XM_011531684.4 | c.650T>A | p.Leu217Ter | stop_gained | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMAA | ENST00000649156.2 | c.650T>A | p.Leu217Ter | stop_gained | 4/7 | NM_172250.3 | P1 | ||
ENST00000504555.1 | n.254-3246A>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Methylmalonic aciduria, cblA type Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 218976). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 15308131). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu217*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2021 | Variant summary: MMAA c.650T>A (p.Leu217X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251418 control chromosomes. c.650T>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (e.g. Yang_2004, Tang_2020). These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at