rs1057517759
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_000429.3(MAT1A):c.964A>T(p.Ile322Phe) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I322M) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000429.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAT1A | NM_000429.3 | c.964A>T | p.Ile322Phe | missense_variant | 8/9 | ENST00000372213.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAT1A | ENST00000372213.8 | c.964A>T | p.Ile322Phe | missense_variant | 8/9 | 1 | NM_000429.3 | P1 | |
MAT1A | ENST00000480845.1 | n.196A>T | non_coding_transcript_exon_variant | 2/5 | 3 | ||||
MAT1A | ENST00000485270.5 | n.476A>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2016 | The I322F variant in the MAT1A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the I322F variant is a conservative amino acid change, this position is conserved across species and two other conservative missense variants at this position (I322M, I322V) have been reported in association with methionine adenosyltransferase I/III (MAT I/III) deficiency (Ubagai et al. 1995; Fernández-Irigoyen et al. 2010). Expression studies found that both the I322M and I322V variants were associated with reduced methionine adenosyltransferase I/III activity (Ubagai et al. 1995; Fernández-Irigoyen et al. 2010). In summary, we interpret I322F to be a pathogenic variant. - |
Hepatic methionine adenosyltransferase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2018 | This sequence change replaces isoleucine with phenylalanine at codon 322 of the MAT1A protein (p.Ile322Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MAT1A-related disease. ClinVar contains an entry for this variant (Variation ID: 372407). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.Ile322Val, p.Ile322Met) have been reported in the homozygous state and in combination with another MAT1A variant in individuals affected with MAT1A-deficiency (PMID: 20675163, 7560086). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at