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GeneBe

rs2236225

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. 10/16 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

2
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O: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]

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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/exons MANE UniProt
MTHFD1NM_005956.4 linkuse as main transcriptc.1958G>A p.Arg653Gln missense_variant 20/28 ENST00000652337.1
MTHFD1NM_001364837.1 linkuse as main transcriptc.1958G>A p.Arg653Gln missense_variant 20/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFD1ENST00000652337.1 linkuse as main transcriptc.1958G>A p.Arg653Gln missense_variant 20/28 NM_005956.4 P1
ENST00000609125.1 linkuse as main transcriptn.112C>T non_coding_transcript_exon_variant 1/1
ENST00000556640.1 linkuse as main transcriptn.505+5926C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.387
AC:
58706
AN:
151876
Hom.:
12553
Cov.:
32
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.:
47
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.:
32
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:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 03, 2021- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 09, 2021This variant is associated with the following publications: (PMID: 24977710, 23685927, 12384833, 25525159, 16123074, 24368157, 18767138, 16552426, 21615938) -
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Neural tube defects, folate-sensitive, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMMar 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.43
Cadd
Benign
22
Dann
Uncertain
1.0
Eigen
Benign
0.0034
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.93
D
MetaRNN
Benign
0.00016
T;T
MetaSVM
Benign
-0.91
T
MutationTaster
Benign
0.029
P;P;P
PrimateAI
Benign
0.46
T
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
T
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.

Other links and lift over

dbSNP: rs2236225; hg19: chr14-64908845; COSMIC: COSV53697812; COSMIC: COSV53697812; API