chr10-80283967-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000429.3(MAT1A):c.241C>T(p.Arg81Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000429.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251366Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135856
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727238
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:3
Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
The MAT1A p.Arg81Trp variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs750570720) and Clinvar (classified as a variant of uncertain significance by Illumina, Invitae and ARUP Laboratories for hepatic methionine adenosyltransferase deficiency). The variant was identified in control databases in 14 of 282762 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 3 of 10366 chromosomes (freq: 0.000289), Latino in 9 of 35426 chromosomes (freq: 0.000254) and European (non-Finnish) in 2 of 129098 chromosomes (freq: 0.000015); it was not observed in the African, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a change in splicing. The p.Arg81 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
The p.Arg81Trp variant (rs750570720) has not been reported in the medical literature or gene specific variation databases but has been reported to ClinVar (Variation ID: 301190). This variant is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.002 percent (identified on 2 out of 121,086 chromosomes). The arginine at position 81 is moderately conserved (considering 15 species) and computational analyses of the effects of the p.Arg81Trp variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Arg81Trp variant with certainty. -
Hepatic methionine adenosyltransferase deficiency Uncertain:2
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 81 of the MAT1A protein (p.Arg81Trp). This variant is present in population databases (rs750570720, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAT1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 301190). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAT1A protein function with a negative predictive value of 80%. 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. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Inborn genetic diseases Uncertain:1
The c.241C>T (p.R81W) alteration is located in exon 3 (coding exon 3) of the MAT1A gene. This alteration results from a C to T substitution at nucleotide position 241, causing the arginine (R) at amino acid position 81 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at