rs200908035
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.566A>T(p.Asn189Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N189K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000255.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.566A>T | p.Asn189Ile | missense_variant | 3/13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.566A>T | p.Asn189Ile | missense_variant | 3/13 | XP_005249200.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.566A>T | p.Asn189Ile | missense_variant | 3/13 | 1 | NM_000255.4 | ENSP00000274813.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251196Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461558Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727140
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 16, 2021 | NM_000255.3(MMUT):c.566A>T(N189I) is a missense variant classified as likely pathogenic in the context of methylmalonic acidemia, MMUT-related. N189I has been observed in cases with relevant disease (PMID: 27167370, 27233228). Functional assessments of this variant are available in the literature (PMID: 27167370). Internal structural analysis of the variant is supportive of pathogenicity. N189I has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000255.3(MMUT):c.566A>T(N189I) is a missense variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | University Children's Hospital, University of Zurich | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 14, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 08, 2023 | ClinVar contains an entry for this variant (Variation ID: 222915). For these reasons, this variant has been classified as Pathogenic. 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 MUT protein function. This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 27167370, 27233228). This variant is present in population databases (rs200908035, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 189 of the MUT protein (p.Asn189Ile). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at