Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005957(MTHFR):c.1958C>T(p.Thr653Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 152192 control chromosomes in the gnomAD Genomes database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T653T) has been classified as Likely benign.
Verdict is Benign. Variant got -20 ACMG points.
GnomAD3 genomes AF: 0.0141AC: 2146AN: 152192Hom.: 24Cov.: 33 GnomAD3 exomes AF: 0.0137AC: 3432AN: 251292Hom.: 29 AF XY: 0.0137AC XY: 1865AN XY: 135806 GnomAD4 exome AF: 0.0194AC: 28383AN: 1461852Hom.: 323 AF XY: 0.0191AC XY: 13902AN XY: 727218
Submissions by phenotype
|Benign, criteria provided, single submitter||clinical testing||Eurofins Ntd Llc (ga)||Jul 13, 2015||- -|
|Benign, no assertion criteria provided||clinical testing||Clinical Genetics, Academic Medical Center||-||- -|
|Benign, no assertion criteria provided||clinical testing||Genome Diagnostics Laboratory, University Medical Center Utrecht||-||- -|
|Likely benign, no assertion criteria provided||clinical testing||Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+||-||- -|
|Benign, criteria provided, single submitter||clinical testing||ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories||Apr 17, 2020||- -|
|Benign, criteria provided, single submitter||clinical testing||GeneDx||Apr 16, 2018||This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -|
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
|Benign, criteria provided, single submitter||clinical testing||Invitae||Nov 02, 2022||- -|
|Benign, criteria provided, single submitter||clinical testing||Genome-Nilou Lab||Jun 10, 2021||- -|
|Benign, no assertion criteria provided||clinical testing||Natera, Inc.||Sep 16, 2020||- -|
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