rs1801131
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1
The NM_005957(MTHFR):c.1286A>C(p.Glu429Ala) variant causes a missense change. The variant allele was found at a frequency of 0.263 in 151880 control chromosomes in the gnomAD Genomes database, including 5754 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity,other (★).
Frequency
Genomes: 𝑓 0.26 ( 5754 hom., cov: 31)
Exomes 𝑓: 0.29 ( 11567 hom. )
Consequence
MTHFR
NM_005957 missense
NM_005957 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 3.76
Links
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0029579103).
BP6
?
Variant 1:11794419-T>G is Benign according to our data. Variant chr1-11794419-T-G is described in ClinVar as [Conflicting_interpretations_of_pathogenicity, other]. Clinvar id is 3521. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Likely_pathogenic=1, Uncertain_significance=1, other=1}. Variant chr1-11794419-T-G is described in Lovd as [Benign].
BA1
?
GnomAd highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.1286A>C | p.Glu429Ala | missense_variant | 8/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.1286A>C | p.Glu429Ala | missense_variant | 8/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.263 AC: 40003AN: 151880Hom.: 5754 Cov.: 31
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GnomAD3 exomes AF: 0.289 AC: 72672AN: 251462Hom.: 11567 AF XY: 0.301 AC XY: 40915AN XY: 135908
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ESP6500AA
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ClinVar
Significance: Conflicting interpretations of pathogenicity; other
Submissions summary: Pathogenic:1Uncertain:2Benign:13Other:2
Revision: criteria provided, conflicting interpretations
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 28, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Benign:3Other:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | Criteria applied: BS1 - |
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 13, 2017 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2021 | E429A, commonly reported as c.1298A>C, is a benign variant. It results in reduced MTHFR activity but it is not associated with increased plasma folate concentration in the heterozygous or homozygous state. This variant is present in 31% of alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9545395, 18842806, 21241403, 22882325, 18836720, 21577095, 20135343, 23652803, 18992148, 23162020, 23771968, 19936946, 19837268, 20031554, 19232336, 19356065, 11875032, 22102315, 21897766, 21334398, 21845428, 20935396, 20532637, 21080081, 18583979, 21613384, 19854238, 21107737, 11395038, 9719624, 26238013, 27068821, 27330833, 23659764, 24109560, 23685927, 11274424, 29600437, 24440586, 22051736, 29395581, 20078877, 24175756, 24488901, 24301776, 22576927, 25573130, 29974397, 26135458, 23523621, 16489479) - |
Stroke Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jun 23, 2021 | ACMG categories: PS3,PS4,PM1,BA1 - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, no assertion criteria provided | case-control | Department of Pharmacy and Biotechnology, University of Bologna | - | - - |
Neural tube defects, folate-sensitive Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
MTHFR THERMOLABILE POLYMORPHISM Benign:1
Benign, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Schizophrenia, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L;.;.;.
MutationTaster
Benign
P;P;P;P
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;.;.
REVEL
Benign
Sift
Benign
T;T;T;T;.;.;.
Sift4G
Benign
T;T;T;T;.;.;.
Polyphen
B;.;.;B;.;.;.
Vest4
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Find out SpliceAI and Pangolin per-transcript scores at