rs2236225

chr14-64442127-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.26

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]

(HGNC:):

ACMG classification

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
MTHFD1	NM_005956.4	c.1958G>A	p.Arg653Gln	missense_variant	20/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.1958G>A	p.Arg653Gln	missense_variant	20/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.1958G>A	p.Arg653Gln	missense_variant	20/28		NM_005956.4	P1
	ENST00000609125.1	n.112C>T		non_coding_transcript_exon_variant	1/1
	ENST00000556640.1	n.505+5926C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58706 AN: 151876 Hom.: 12553 Cov.: 32

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

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

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

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided Benign:2

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	Invitae	Feb 01, 2024	- -

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	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

Other links and lift over

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