Menu
GeneBe

rs1801131

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005957.5(MTHFR):c.1286A>C(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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.26 ( 5754 hom., cov: 31)
Exomes 𝑓: 0.31 ( 71219 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

4
13

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1U:1B:17O:2

Conservation

PhyloP100: 3.76
Variant links:
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]

Genome browser will be placed here

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, 4 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
MTHFRNM_005957.5 linkuse as main transcriptc.1286A>C p.Glu429Ala missense_variant 8/12 ENST00000376590.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFRENST00000376590.9 linkuse as main transcriptc.1286A>C p.Glu429Ala missense_variant 8/121 NM_005957.5 A1P42898-1

Frequencies

GnomAD3 genomes
AF:
0.263
AC:
40003
AN:
151880
Hom.:
5754
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.167
Gnomad AMI
AF:
0.219
Gnomad AMR
AF:
0.207
Gnomad ASJ
AF:
0.297
Gnomad EAS
AF:
0.221
Gnomad SAS
AF:
0.407
Gnomad FIN
AF:
0.328
Gnomad MID
AF:
0.366
Gnomad NFE
AF:
0.316
Gnomad OTH
AF:
0.271
GnomAD3 exomes
AF:
0.289
AC:
72672
AN:
251462
Hom.:
11567
AF XY:
0.301
AC XY:
40915
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.158
Gnomad AMR exome
AF:
0.159
Gnomad ASJ exome
AF:
0.294
Gnomad EAS exome
AF:
0.220
Gnomad SAS exome
AF:
0.412
Gnomad FIN exome
AF:
0.319
Gnomad NFE exome
AF:
0.319
Gnomad OTH exome
AF:
0.296
GnomAD4 exome
AF:
0.307
AC:
449260
AN:
1461544
Hom.:
71219
Cov.:
49
AF XY:
0.311
AC XY:
226409
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.157
Gnomad4 AMR exome
AF:
0.167
Gnomad4 ASJ exome
AF:
0.292
Gnomad4 EAS exome
AF:
0.205
Gnomad4 SAS exome
AF:
0.411
Gnomad4 FIN exome
AF:
0.314
Gnomad4 NFE exome
AF:
0.313
Gnomad4 OTH exome
AF:
0.305
GnomAD4 genome
AF:
0.263
AC:
40027
AN:
151998
Hom.:
5754
Cov.:
31
AF XY:
0.265
AC XY:
19654
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.167
Gnomad4 AMR
AF:
0.207
Gnomad4 ASJ
AF:
0.297
Gnomad4 EAS
AF:
0.221
Gnomad4 SAS
AF:
0.408
Gnomad4 FIN
AF:
0.328
Gnomad4 NFE
AF:
0.316
Gnomad4 OTH
AF:
0.270
Alfa
AF:
0.302
Hom.:
12545
Bravo
AF:
0.246
TwinsUK
AF:
0.325
AC:
1205
ALSPAC
AF:
0.313
AC:
1207
ESP6500AA
AF:
0.155
AC:
683
ESP6500EA
AF:
0.313
AC:
2693
ExAC
AF:
0.295
AC:
35807
Asia WGS
AF:
0.304
AC:
1057
AN:
3478
EpiCase
AF:
0.314
EpiControl
AF:
0.309

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 submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Likely pathogenic, flagged submissionclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 28, 2019This 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, criteria provided, single submitterclinical testingGenome-Nilou LabJul 01, 2021- -
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterDec 06, 2023ACMG categories: BA1, BP4 -
not specified Benign:6
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 07, 2023Variant 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:3Other:1
other, criteria provided, single submitterclinical testingEurofins 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023MTHFR: BP4, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 25, 2021E429A, 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) -
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, flagged submissioncase-controlDepartment of Pharmacy and Biotechnology, University of Bologna-- -
Neural tube defects, folate-sensitive Benign:1
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
MTHFR THERMOLABILE POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
MTHFR-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 01, 2023This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Schizophrenia, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.23
Cadd
Benign
19
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;.;.;D;.;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.061
FATHMM_MKL
Uncertain
0.96
D
MetaRNN
Benign
0.0030
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;.;.;L;.;.;.
MutationTaster
Benign
0.0000017
P;P;P;P
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.1
D;D;D;D;.;.;.
REVEL
Benign
0.20
Sift
Benign
0.10
T;T;T;T;.;.;.
Sift4G
Benign
0.20
T;T;T;T;.;.;.
Polyphen
0.021
B;.;.;B;.;.;.
Vest4
0.21
MPC
0.28
ClinPred
0.019
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.21
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1801131; hg19: chr1-11854476; COSMIC: COSV57171183; COSMIC: COSV57171183; API