rs1801131

Positions:

chr1-11794419-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 12/20 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

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]

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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 [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	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.1286A>C	p.Glu429Ala	missense_variant	8/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.1286A>C	p.Glu429Ala	missense_variant	8/12	1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

40003

AN:

151880

Hom.:

5754

Cov.:

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.:

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.:

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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 06, 2023	ACMG categories: BA1, BP4 -

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	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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	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) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MTHFR: BP4, BS1, BS2 -

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, no assertion criteria provided

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;.;.;D;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

.;T;.;T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;L;.;.;.

MutationTaster

Benign

0.0000017

P;P;P;P

PrimateAI

Benign

0.47

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over