1-11790870-C-T

Position:

chr1-11790870-C-T

Variant summary

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

The ENST00000376590.9(MTHFR):c.1781G>A(p.Arg594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,878 control chromosomes in the GnomAD database, including 2,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R594W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.044 ( 231 hom., cov: 33)

Exomes 𝑓: 0.053 ( 2697 hom. )

Consequence

MTHFR
ENST00000376590.9 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 3.20

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 -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 ENST00000376590.9

BP4

Computational evidence support a benign effect (MetaRNN=0.0017618239).

BP6

Variant 1-11790870-C-T is Benign according to our data. Variant chr1-11790870-C-T is described in ClinVar as [Benign, other]. Clinvar id is 194071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11790870-C-T is described in Lovd as [Pathogenic]. Variant chr1-11790870-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.139 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.1781G>A	p.Arg594Gln	missense_variant	12/12	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.1781G>A	p.Arg594Gln	missense_variant	12/12	1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0443

AC:

6735

AN:

151930

Hom.:

230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0430

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0463

Gnomad OTH

AF:

0.0431

GnomAD3 exomes

AF:

0.0555

AC:

13949

AN:

251250

Hom.:

651

AF XY:

0.0580

AC XY:

7884

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.0282

Gnomad AMR exome

AF:

0.0434

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.117

Gnomad SAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0442

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0535

AC:

78138

AN:

1461830

Hom.:

2697

Cov.:

AF XY:

0.0552

AC XY:

40131

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0256

Gnomad4 AMR exome

AF:

0.0428

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.128

Gnomad4 FIN exome

AF:

0.0184

Gnomad4 NFE exome

AF:

0.0494

Gnomad4 OTH exome

AF:

0.0606

GnomAD4 genome

AF:

0.0443

AC:

6739

AN:

152048

Hom.:

231

Cov.:

AF XY:

0.0444

AC XY:

3300

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0305

Gnomad4 AMR

AF:

0.0431

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.148

Gnomad4 FIN

AF:

0.0160

Gnomad4 NFE

AF:

0.0463

Gnomad4 OTH

AF:

0.0436

Alfa

AF:

0.0462

Hom.:

487

Bravo

AF:

0.0427

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.0297

AC:

131

ESP6500EA

AF:

0.0462

AC:

397

ExAC

AF:

0.0562

AC:

6823

Asia WGS

AF:

0.127

AC:

441

AN:

3478

EpiCase

AF:

0.0387

EpiControl

AF:

0.0410

ClinVar

Significance: Benign; other

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 528/13006=4.05% -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MTHFR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.13

T;.;.;T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.73

.;T;.;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.;.;N;.;.

MutationTaster

Benign

0.99

P;P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

1.4

N;N;N;N;.;.

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;.;.

Polyphen

0.0

B;.;.;B;.;.

Vest4

0.044

MPC

0.30

ClinPred

0.0089

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.042

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -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