rs370444838
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_005956.4(MTHFD1):c.146C>T(p.Ser49Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,612,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
MTHFD1
NM_005956.4 missense
NM_005956.4 missense
Scores
7
6
4
Clinical Significance
Conservation
PhyloP100: 7.02
Genes affected
MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a mutagenesis_site Reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity by 75%. Reduced methenyltetrahydrofolate cyclohydrolase activity by 99%. No effect on affinity for NADP and 5,10-methenyltetrahydrofolate. (size 0) in uniprot entity C1TC_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-64411109-C-T is Pathogenic according to our data. Variant chr14-64411109-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFD1 | NM_005956.4 | c.146C>T | p.Ser49Phe | missense_variant | 3/28 | ENST00000652337.1 | |
MTHFD1 | NM_001364837.1 | c.146C>T | p.Ser49Phe | missense_variant | 3/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFD1 | ENST00000652337.1 | c.146C>T | p.Ser49Phe | missense_variant | 3/28 | NM_005956.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251122Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135766
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GnomAD4 exome AF: 0.000203 AC: 296AN: 1460654Hom.: 0 Cov.: 30 AF XY: 0.000201 AC XY: 146AN XY: 726766
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74330
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 12, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Likely Pathogenic, for Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM2-Supporting => PM2 downgraded in strength to Supporting. - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 03, 2021 | Variant summary: MTHFD1 c.146C>T (p.Ser49Phe) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (IPR020630) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251122 control chromosomes (gnomAD v2.1, exomes dataset). This frequency is not higher than the maximum expected for a pathogenic variant in MTHFD1 causing Severe Combined Immunodeficiency Syndrome (0.00035), allowing no conclusion about variant significance. c.146C>T has been reported in the literature in at least 5 individuals from two families who were affected with combined immunodeficiency and megaloblastic anemia (Burda_2015, Bidla_2020), of note the variant co-segregated with disease in these families. These data indicate that the variant is likely to be associated with disease. Publications also reports experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity in patient derived fibroblast (Burda_2015, Bidla_2020). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the MTHFD1 protein (p.Ser49Phe). This variant is present in population databases (rs370444838, gnomAD 0.02%). This missense change has been observed in individual(s) with methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 25633902, 32414565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTHFD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Uncertain
Sift
Benign
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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