1-11794419-T-G
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_005957.5(MTHFR):āc.1286A>Cā(p.Glu429Ala) variant causes a missense change. The variant allele was found at a frequency of 0.303 in 1,613,542 control chromosomes in the GnomAD database, including 76,973 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (ā ā ).
Frequency
Genomes: š 0.26 ( 5754 hom., cov: 31)
Exomes š: 0.31 ( 71219 hom. )
Consequence
MTHFR
NM_005957.5 missense
NM_005957.5 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 3.76
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 Benign. Variant got -18 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_005957.5
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 [Likely_benign, other]. Clinvar id is 3521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794419-T-G is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 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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GnomAD4 exome AF: 0.307 AC: 449260AN: 1461544Hom.: 71219 Cov.: 49 AF XY: 0.311 AC XY: 226409AN XY: 727098
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GnomAD4 genome ? AF: 0.263 AC: 40027AN: 151998Hom.: 5754 Cov.: 31 AF XY: 0.265 AC XY: 19654AN XY: 74288
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ESP6500AA
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ClinVar
Significance: Benign/Likely benign; other
Submissions summary: Pathogenic:1Uncertain:1Benign:17Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1Benign:5
Benign, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 06, 2023 | ACMG categories: BA1, BP4 - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 01, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely pathogenic, flagged submission | 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. - |
not specified Benign:6
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 | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2023 | Variant summary: MTHFR c.1286A>C (p.Glu429Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.29 in 251462 control chromosomes in the gnomAD database, including 11567 homozygotes strongly suggesting that the variant is benign. This variant, c.1286A>C is also known as 1298A>C. One publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and homocysteine levels for heterozygotes and homozygotes were not different from those with the wild type genotype, supporting the idea that this polymorphism alone might not significantly affect homocysteine metabolism (example: Weisberg_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11395038). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as Benign/likely benign (n=7), uncertain significance (n=1), risk factor (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3Other:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | MTHFR: BP4, BS1, BS2 - |
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) - |
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 | Nov 29, 2023 | - - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, flagged submission | case-control | Department of Pharmacy and Biotechnology, University of Bologna | - | - - |
MTHFR-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 01, 2023 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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
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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