rs370444838

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_005956.4(MTHFD1):c.146C>T(p.Ser49Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,612,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

MTHFD1
NM_005956.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a mutagenesis_site Reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity by 75%. Reduced methenyltetrahydrofolate cyclohydrolase activity by 99%. No effect on affinity for NADP and 5,10-methenyltetrahydrofolate. (size 0) in uniprot entity C1TC_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-64411109-C-T is Pathogenic according to our data. Variant chr14-64411109-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4 linkuse as main transcript	c.146C>T	p.Ser49Phe	missense_variant	3/28	ENST00000652337.1
MTHFD1	NM_001364837.1 linkuse as main transcript	c.146C>T	p.Ser49Phe	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1 linkuse as main transcript	c.146C>T	p.Ser49Phe	missense_variant	3/28		NM_005956.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251122

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1460654

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000105

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM2-Supporting => PM2 downgraded in strength to Supporting. -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 03, 2021

Variant summary: MTHFD1 c.146C>T (p.Ser49Phe) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (IPR020630) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251122 control chromosomes (gnomAD v2.1, exomes dataset). This frequency is not higher than the maximum expected for a pathogenic variant in MTHFD1 causing Severe Combined Immunodeficiency Syndrome (0.00035), allowing no conclusion about variant significance. c.146C>T has been reported in the literature in at least 5 individuals from two families who were affected with combined immunodeficiency and megaloblastic anemia (Burda_2015, Bidla_2020), of note the variant co-segregated with disease in these families. These data indicate that the variant is likely to be associated with disease. Publications also reports experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity in patient derived fibroblast (Burda_2015, Bidla_2020). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the MTHFD1 protein (p.Ser49Phe). This variant is present in population databases (rs370444838, gnomAD 0.02%). This missense change has been observed in individual(s) with methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 25633902, 32414565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTHFD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

-0.24

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.7

D;D;.

REVEL

Uncertain

0.44

Sift

Benign

0.040

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.88

MVP

0.64

MPC

1.2

ClinPred

0.98

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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