rs1801131

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_005957(MTHFR):c.1286A>C(p.Glu429Ala) variant causes a missense change. The variant allele was found at a frequency of 0.263 in 151880 control chromosomes in the gnomAD Genomes database, including 5754 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 Conflicting interpretations of pathogenicity,other (★).

Frequency

Genomes: 𝑓 0.26 ( 5754 hom., cov: 31)

Exomes 𝑓: 0.29 ( 11567 hom. )

Consequence

MTHFR
NM_005957 missense

Scores

Clinical Significance

Conflicting interpretations of pathogenicity; other criteria provided, conflicting interpretations P:1U:2B:13O:2

Conservation

PhyloP100: 3.76

Links

MTHFR (HGNC:7436):

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 [Conflicting_interpretations_of_pathogenicity, other]. Clinvar id is 3521. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Likely_pathogenic=1, Uncertain_significance=1, other=1}. Variant chr1-11794419-T-G is described in Lovd as [Benign].

BA1

GnomAd highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	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 linkuse as main transcript	c.1286A>C	p.Glu429Ala	missense_variant	8/12	1	NM_005957.5	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

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

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: Conflicting interpretations of pathogenicity; other

Submissions summary: Pathogenic:1Uncertain:2Benign:13Other:2

Revision: criteria provided, conflicting interpretations

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	Criteria applied: BS1 -
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	Oct 25, 2022	- -
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) -

Stroke

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jun 23, 2021

ACMG categories: PS3,PS4,PM1,BA1 -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

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

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

Find out SpliceAI 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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over