rs779094715
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000429.3(MAT1A):c.745C>T(p.Arg249Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,794 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 (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
MAT1A
NM_000429.3 missense
NM_000429.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
MAT1A (HGNC:6903): (methionine adenosyltransferase 1A) This gene catalyzes a two-step reaction that involves the transfer of the adenosyl moiety of ATP to methionine to form S-adenosylmethionine and tripolyphosphate, which is subsequently cleaved to PPi and Pi. S-adenosylmethionine is the source of methyl groups for most biological methylations. The encoded protein is found as a homotetramer (MAT I) or a homodimer (MAT III) whereas a third form, MAT II (gamma), is encoded by the MAT2A gene. Mutations in this gene are associated with methionine adenosyltransferase deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000429.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.979
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAT1A | NM_000429.3 | c.745C>T | p.Arg249Trp | missense_variant | 6/9 | ENST00000372213.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAT1A | ENST00000372213.8 | c.745C>T | p.Arg249Trp | missense_variant | 6/9 | 1 | NM_000429.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251034Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135744
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727206
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GnomAD4 genome ? Cov.: 33
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?
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33
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ExAC
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6
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hepatic methionine adenosyltransferase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2018 | This sequence change replaces arginine with tryptophan at codon 249 of the MAT1A protein (p.Arg249Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs779094715, ExAC 0.04%). This variant has been reported as heterozygous in an individual affected with hypermethioninemia (PMID: 15935930). Experimental studies have shown that this missense change causes a reduction in MAT enzymatic activity to approximately 20% of the wild-type level (PMID: 20675163). Structural studies have shown that this variant resides in the dimer interface of the protein. Variants localized in this region or in the substrate binding site have been associated with the autosomal dominant form of disease due to their disruption of the dimerization of the protein or substrate binding, whereas autosomal recessive variants are located elsewhere in the protein (PMID: 23425511, 26933843, 28748147). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of methylation at R249 (P = 0.0209);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at