rs1801131

chr1-11794419-T-G

Variant summary

Our verdict is Benign. Variant got -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. 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
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1 U:1 B:17 O:2
• 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]

ACMG classification

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
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: 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

GnomAD3 exomes AF: 0.289 AC: 72672 AN: 251462 Hom.: 11567 AF XY: 0.301 AC XY: 40915 AN XY: 135908

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

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

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:1 Uncertain:1 Benign:17 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3 Other:1

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

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: 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

Other links and lift over

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