rs2236225

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653W) has been classified as Uncertain significance.

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

Publications

379 publications found

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 Gene-Disease associations (from GenCC):

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MTHFD1 links:

ENSG00000272909 (HGNC:):

ENSG00000272909 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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
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

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

GnomAD2 exomes

AF:

0.444

AC:

111611

AN:

251462

AF XY:

0.448

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 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

African (AFR)

AF:

0.203

AC:

6797

AN:

33474

American (AMR)

AF:

0.575

AC:

25737

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

11429

AN:

26128

East Asian (EAS)

AF:

0.259

AC:

10275

AN:

39700

South Asian (SAS)

AF:

0.518

AC:

44656

AN:

86244

European-Finnish (FIN)

AF:

0.453

AC:

24205

AN:

53418

Middle Eastern (MID)

AF:

0.421

AC:

2428

AN:

5768

European-Non Finnish (NFE)

AF:

0.454

AC:

504751

AN:

1111654

Other (OTH)

AF:

0.430

AC:

25955

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

22442

44885

67327

89770

112212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15074

30148

45222

60296

75370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.386

AC:

58737

AN:

151994

Hom.:

12554

Cov.:

AF XY:

0.389

AC XY:

28908

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.212

AC:

8776

AN:

41482

American (AMR)

AF:

0.519

AC:

7935

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

1514

AN:

3470

East Asian (EAS)

AF:

0.221

AC:

1142

AN:

5156

South Asian (SAS)

AF:

0.505

AC:

2427

AN:

4808

European-Finnish (FIN)

AF:

0.446

AC:

4698

AN:

10538

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30752

AN:

67958

Other (OTH)

AF:

0.395

AC:

830

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1724

3448

5173

6897

8621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.426

Hom.:

46692

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

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24977710, 23685927, 12384833, 25525159, 16123074, 24368157, 18767138, 16552426, 21615938) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 03, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neural tube defects, folate-sensitive, susceptibility to

Other:1

Mar 01, 2008

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

5.3

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

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over