rs34181110

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005956.4(MTHFD1):c.878G>A(p.Arg293His) variant causes a missense change. The variant allele was found at a frequency of 0.00265 in 1,612,896 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

MTHFD1
NM_005956.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 3.74

Publications

12 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:

ENSG00000258824 (HGNC:):

ENSG00000258824 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009117931).

BP6

Variant 14-64425752-G-A is Benign according to our data. Variant chr14-64425752-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13632.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152242) while in subpopulation NFE AF = 0.00319 (217/68014). AF 95% confidence interval is 0.00284. There are 7 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4 link	c.878G>A	p.Arg293His	missense_variant	Exon 10 of 28	ENST00000652337.1	NP_005947.3	P11586
MTHFD1	NM_001364837.1 link	c.878G>A	p.Arg293His	missense_variant	Exon 10 of 27		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 link	c.878G>A	p.Arg293His	missense_variant	Exon 10 of 28		NM_005956.4	ENSP00000498336.1		P11586

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00319

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00167

AC:

421

AN:

251428

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00273

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00268

AC:

3914

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1895

AN XY:

726644

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33456

American (AMR)

AF:

0.000581

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000464

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000410

AC:

AN:

4882

European-Non Finnish (NFE)

AF:

0.00314

AC:

3487

AN:

1111854

Other (OTH)

AF:

0.00377

AC:

227

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

196

393

589

786

982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00240

AC:

365

AN:

152242

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41548

American (AMR)

AF:

0.00118

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00319

AC:

217

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00260

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00154

AC:

187

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MTHFD1: BP4 -

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Uncertain:1

Aug 16, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MTHFD1 NM_005956.3 exon 10 p.Arg293His (c.878G>A): This variant has been reported in the literature in 1 individual in association with neural tube defects, segregating with disease in 1 affected family member (Hol 1998 PMID:9611072). This variant is present in 0.3% (217/68022) of European alleles and in 7 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/14-64425752-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 13632). This variant amino acid (Histidine) is present in several species including multiple mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spina bifida, folate-sensitive, susceptibility to

Other:1

Feb 01, 1998

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

0.081

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.84

PhyloP100

3.7

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.0

D;.

REVEL

Benign

0.24

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.025

D;D

Polyphen

0.040

B;.

Vest4

0.70

MVP

0.90

MPC

0.45

ClinPred

0.036

GERP RS

2.2

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs34181110

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