rs138556525
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000429.3(MAT1A):c.776C>T(p.Ala259Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,750 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.
Frequency
Consequence
NM_000429.3 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 |
---|---|---|---|---|---|---|---|
MAT1A | NM_000429.3 | c.776C>T | p.Ala259Val | missense_variant | 7/9 | ENST00000372213.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAT1A | ENST00000372213.8 | c.776C>T | p.Ala259Val | missense_variant | 7/9 | 1 | NM_000429.3 | P1 | |
MAT1A | ENST00000480845.1 | n.8C>T | non_coding_transcript_exon_variant | 1/5 | 3 | ||||
MAT1A | ENST00000485270.5 | n.288C>T | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247466Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134184
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1459750Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5AN XY: 726106
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hepatic methionine adenosyltransferase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the MAT1A protein (p.Ala259Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant hypermethioninemia (PMID: 20675163, 24445979, 28748147; Invitae). ClinVar contains an entry for this variant (Variation ID: 279845). 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 not expected to disrupt MAT1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAT1A function (PMID: 23425511, 26933843, 28748147). For these reasons, this variant has been classified as Pathogenic. - |
MAT1A-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 15, 2023 | The MAT1A c.776C>T variant is predicted to result in the amino acid substitution p.Ala259Val. This variant has previously been reported in two presumably unrelated patients with hypermethioninemia (Fernández-Irigoyen et al. 2010. PubMed ID: 20675163; Chadwick et al. 2014. PubMed ID: 24445979). The patient reported by Fernández-Irigoyen had greatly decreased methionine adenosyltransferase I/III activity. Additionally, a parent-child pair was reported with both individuals carrying this variant in the heterozygous state. In this family, the mother was also found to exhibit hypermethioninemia. As a result, the authors suggested that this variant may cause autosomal dominant hypermethioninemia (Muriello et al. 2017. PubMed ID: 28748147). In a recent study, four additional patients with hypermethioninemia were reported to harbor this variant in the heterozygous state alone, consistent with autosomal dominant inheritance (Tong et al. 2022. PubMed ID: 36704196). The p.Ala259Val amino acid is predicted to affect protein dimerization, similarly to the commonly reported autosomal dominant p.Arg264His change and other residues localized to the dimer interface (Shafqat et al. 2013. PubMed ID: 23425511; Kim et al. 2016. PubMed ID: 26933843; Muriello et al. 2017. PubMed ID: 28748147). In an expression study in E. coli cells, the p.Ala259Val substitution decreased the methionine adenosyltransferase enzyme activity to less than 20% of control (Fernández-Irigoyen et al. 2010. PubMed ID: 20675163). This variant is reported in 0.0064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-82034948-G-A). Taken together, we classify this variant as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2020 | Expression studies found that A259V was associated with an approximately 80-95% reduction in methionine adenosyltransferase (MATI/III) activity compared with wild-type enzyme while tripolyphosphatase activity, the second step in the reaction catalyzed by MAT I/III enzyme, was only slightly reduced (Fernandez-Irigoyet et al., 2010); Majority of MAT1A pathogenic variants are inherited in an autosomal recessive manner; however, dominant inheritance has been well documented for a single R264H missense variant. At this time, there is not enough evidence to support A259V as a dominant variant (Fernandez-Irigoyet et al., 2010); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 32335878, 20675163, 24445979, 23425511, 26933843, 28748147, 28492532, 31737040) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at