rs746353274
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_005957.5(MTHFR):c.643_645delAAG(p.Lys215del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005957.5 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461040Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726852
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1Uncertain:1
This variant, c.643_645del, results in the deletion of 1 amino acid(s) of the MTHFR protein (p.Lys215del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746353274, gnomAD 0.002%). This variant has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency or homocystinuria (PMID: 25736335, 27768236). ClinVar contains an entry for this variant (Variation ID: 187878). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
- -
not specified Uncertain:1
Variant summary: MTHFR c.643_645delAAG (p.Lys215del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251490 control chromosomes. c.643_645delAAG has been reported in the literature in individuals affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency. In one case, the variant was reported in a patient with hyperhomocysteinemia who had less than 1.5% residual MTHFR activity in cultured fibroblasts cell lines, but also carried an additional MTHFR variant (c.391C>T), making conclusions about the functional significance of the variant of interest difficult to assess (Bruda_2015). Additonally, the variant was reported in a patient referred for pharmacogenetic analysis prior to chemotherapy initiation, who also displayed hyperhomocysteinemia (Palmirotta_2017). The patient also carried c.677C>T and c.1298A>C, variants known to be associated wiht decreased enzyme activity. Segregation studies showed the probands daughter to carry all three variants and displayed similar hyperhomocysteinemia, while the probands son carried only c.1298A>C as well as the variant of interest, and had normal biochemical values. Thus the authors concluced that the increased plamsa tHcy appeared to be most likely related to the c.677C>T variant, and that the c.643_645delAAG is not suggestive of a pathogenic effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at