rs267606887
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_005957.5(MTHFR):āc.971A>Gā(p.Asn324Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,322 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 Likely pathogenic (ā ). Synonymous variant affecting the same amino acid position (i.e. N324N) has been classified as Likely benign.
Frequency
Consequence
NM_005957.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.971A>G | p.Asn324Ser | missense_variant | 6/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.971A>G | p.Asn324Ser | missense_variant | 6/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461322Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727000
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace asparagine with serine at codon 324 of the MTHFR protein, p.(Asn324Ser). The asparagine residue is evolutionary invariant (100 vertebrates, UCSC), and located in the catalytic domain. There is a small physicochemical difference between asparagine and serine. The variant is absent in a large population cohort (gnomAD v2.1), and has been reported in the homozygous state in at least one case with a biochemically established diagnosis of homocystinuria due to methylenetetrahydrofolate reductase deficiency (PMID: 9781030). In vitro enzymatic assays of the variant demonstrated decreased enzyme activity (further reduced when common polymorphism rs1801133 was in cis), and showed responsiveness to flavin adenine dinucleotide (PMID: 12673793). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PS3_Supporting, PM3_Supporting, PP3, PP4. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at