chr6-49457788-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000255.4(MMUT):āc.656A>Gā(p.Asn219Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,248 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 Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N219Y) has been classified as Pathogenic.
Frequency
Consequence
NM_000255.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.656A>G | p.Asn219Ser | missense_variant | 3/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.656A>G | p.Asn219Ser | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.656A>G | p.Asn219Ser | missense_variant | 3/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251044Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135710
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461054Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726870
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces asparagine with serine at codon 219 of the MUT protein (p.Asn219Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MUT-related conditions. ClinVar contains an entry for this variant (Variation ID: 567826). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Asn219 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11528502, 16281286, 17113806). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 18, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at