1-11792316-AC-A
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_005957.5(MTHFR):c.1593del(p.Lys531AsnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K531K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
MTHFR
NM_005957.5 frameshift
NM_005957.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.680
Genes affected
MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-11792316-AC-A is Pathogenic according to our data. Variant chr1-11792316-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 222897.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.1593del | p.Lys531AsnfsTer13 | frameshift_variant | 10/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.1593del | p.Lys531AsnfsTer13 | frameshift_variant | 10/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | University Children's Hospital, University of Zurich | - | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at