Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PM2_SupportingBP4_Moderate
The NM_005957(MTHFR):c.1952G>A(p.Arg651Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152234 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R651R) has been classified as Likely benign.
Verdict is Likely_benign. Variant got -1 ACMG points.
GnomAD3 genomes AF: 0.00000657AC: 1AN: 152234Hom.: 0Cov.: 33 GnomAD3 exomes AF: 0.00000796AC: 2AN: 251354Hom.: 0 AF XY: 0.00AC XY: 0AN XY: 135852 GnomAD4 exome AF: 0.00000410AC: 6AN: 1461876Hom.: 0 AF XY: 0.00000275AC XY: 2AN XY: 727236
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||May 21, 2022||This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 651 of the MTHFR protein (p.Arg651Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MTHFR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -|
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