rs2236225

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005956.4(MTHFD1):c.1958G>A(p.Arg653Gln) variant causes a missense change. The variant allele was found at a frequency of 0.443 in 1,613,486 control chromosomes in the GnomAD database, including 162,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12554 hom., cov: 32)

Exomes 𝑓: 0.45 ( 150163 hom. )

Consequence

MTHFD1
NM_005956.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 5.26

Variant links:

Genes affected

MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

MTHFD1 links:

ENSG00000272909 (HGNC:):

ENSG00000272909 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=1.6123056E-4).

BP6

Variant 14-64442127-G-A is Benign according to our data. Variant chr14-64442127-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 13633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4 link	c.1958G>A	p.Arg653Gln	missense_variant	Exon 20 of 28	ENST00000652337.1	NP_005947.3	P11586
MTHFD1	NM_001364837.1 link	c.1958G>A	p.Arg653Gln	missense_variant	Exon 20 of 27		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 link	c.1958G>A	p.Arg653Gln	missense_variant	Exon 20 of 28		NM_005956.4	ENSP00000498336.1		P11586

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58706

AN:

151876

Hom.:

12553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.592

Gnomad AMR

AF:

0.519

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.507

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.393

GnomAD3 exomes

AF:

0.444

AC:

111611

AN:

251462

Hom.:

26100

AF XY:

0.448

AC XY:

60904

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.582

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.228

Gnomad SAS exome

AF:

0.520

Gnomad FIN exome

AF:

0.451

Gnomad NFE exome

AF:

0.449

Gnomad OTH exome

AF:

0.442

GnomAD4 exome

AF:

0.449

AC:

656233

AN:

1461492

Hom.:

150163

Cov.:

AF XY:

0.451

AC XY:

328125

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.203

Gnomad4 AMR exome

AF:

0.575

Gnomad4 ASJ exome

AF:

0.437

Gnomad4 EAS exome

AF:

0.259

Gnomad4 SAS exome

AF:

0.518

Gnomad4 FIN exome

AF:

0.453

Gnomad4 NFE exome

AF:

0.454

Gnomad4 OTH exome

AF:

0.430

GnomAD4 genome

AF:

0.386

AC:

58737

AN:

151994

Hom.:

12554

Cov.:

AF XY:

0.389

AC XY:

28908

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.519

Gnomad4 ASJ

AF:

0.436

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.505

Gnomad4 FIN

AF:

0.446

Gnomad4 NFE

AF:

0.453

Gnomad4 OTH

AF:

0.395

Alfa

AF:

0.434

Hom.:

18387

Bravo

AF:

0.381

TwinsUK

AF:

0.453

AC:

1678

ALSPAC

AF:

0.447

AC:

1724

ESP6500AA

AF:

0.214

AC:

943

ESP6500EA

AF:

0.457

AC:

3934

ExAC

AF:

0.435

AC:

52851

Asia WGS

AF:

0.351

AC:

1223

AN:

3478

EpiCase

AF:

0.448

EpiControl

AF:

0.443

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 24977710, 23685927, 12384833, 25525159, 16123074, 24368157, 18767138, 16552426, 21615938) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
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, variant associated with elevated BMI, temporomandibular disorder, neural tube defects, and decreased risk for congenital heart defects. Overall, not convincing. -

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Neural tube defects, folate-sensitive, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.0034

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.00016

T;T

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.12

Sift

Benign

0.17

T;.

Sift4G

Benign

0.15

T;T

Polyphen

0.33

B;.

Vest4

0.059

MPC

0.42

ClinPred

0.022

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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