1-11794419-T-G

Variant names:

• chr1-11794419-T-G
• rs1801131
• NM_005957.5:c.1286A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 13/21 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
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1 U:1 B:19 O:2
• Conservation: PhyloP100: 3.76
• Publications: 3404 publications found

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 Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 Benign/Likely_benign|other. ClinVar VariationId is 3521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1409A>C	p.Glu470Ala	missense	Exon 8 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.1406A>C	p.Glu469Ala	missense	Exon 8 of 12	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1406A>C	p.Glu469Ala	missense	Exon 8 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40003 AN: 151880 Hom.: 5754 Cov.: 31

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

GnomAD2 exomes AF: 0.289 AC: 72672 AN: 251462 AF XY: 0.301

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 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

African (AFR) AF: 0.157 AC: 5264 AN: 33472

American (AMR) AF: 0.167 AC: 7482 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7625 AN: 26136

East Asian (EAS) AF: 0.205 AC: 8131 AN: 39698

South Asian (SAS) AF: 0.411 AC: 35461 AN: 86250

European-Finnish (FIN) AF: 0.314 AC: 16754 AN: 53404

Middle Eastern (MID) AF: 0.373 AC: 2152 AN: 5768

European-Non Finnish (NFE) AF: 0.313 AC: 347994 AN: 1111708

Other (OTH) AF: 0.305 AC: 18397 AN: 60384

GnomAD4 genome AF: 0.263 AC: 40027 AN: 151998 Hom.: 5754 Cov.: 31 AF XY: 0.265 AC XY: 19654 AN XY: 74288

African (AFR) AF: 0.167 AC: 6937 AN: 41452

American (AMR) AF: 0.207 AC: 3162 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1135 AN: 5144

South Asian (SAS) AF: 0.408 AC: 1962 AN: 4812

European-Finnish (FIN) AF: 0.328 AC: 3460 AN: 10554

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21468 AN: 67966

Other (OTH) AF: 0.270 AC: 569 AN: 2108

Alfa AF: 0.297 Hom.: 25769

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:1 Uncertain:1 Benign:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1 Benign:5

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

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.

Dec 06, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: BA1, BP4

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:3 Other:1

Feb 25, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MTHFR: BS1, BS2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2017

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Gastrointestinal stromal tumor Uncertain:1

Department of Pharmacy and Biotechnology, University of Bologna

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: case-control

Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

MTHFR-related disorder Benign:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MTHFR THERMOLABILE POLYMORPHISM Benign:1

Jul 01, 2008

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Schizophrenia, susceptibility to Other:1

Jul 01, 2008

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.021	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
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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