14-64415662-A-G

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.401A>G(p.Lys134Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.823 in 1,612,740 control chromosomes in the GnomAD database, including 547,101 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52492 hom., cov: 33)
  • Exomes 𝑓: 0.82 (494609 hom.)
• Consequence: MTHFD1 NM_005956.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.82

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4773557E-6).
• BP6: Variant 14-64415662-A-G is Benign according to our data. Variant chr14-64415662-A-G is described in ClinVar as [Benign]. Clinvar id is 403114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.401A>G	p.Lys134Arg	missense_variant	6/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.401A>G	p.Lys134Arg	missense_variant	6/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.401A>G	p.Lys134Arg	missense_variant	6/28		NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.829 AC: 126072 AN: 152060 Hom.: 52462 Cov.: 33

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.921

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.845

GnomAD3 exomes AF: 0.835 AC: 208038 AN: 249270 Hom.: 87349 AF XY: 0.838 AC XY: 113124 AN XY: 134934

Gnomad AFR exome AF: 0.848

Gnomad AMR exome AF: 0.909

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.666

Gnomad SAS exome AF: 0.923

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.837

GnomAD4 exome AF: 0.822 AC: 1200499 AN: 1460562 Hom.: 494609 Cov.: 39 AF XY: 0.825 AC XY: 599704 AN XY: 726702

Gnomad4 AFR exome AF: 0.849

Gnomad4 AMR exome AF: 0.908

Gnomad4 ASJ exome AF: 0.839

Gnomad4 EAS exome AF: 0.735

Gnomad4 SAS exome AF: 0.924

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.821

GnomAD4 genome AF: 0.829 AC: 126154 AN: 152178 Hom.: 52492 Cov.: 33 AF XY: 0.828 AC XY: 61607 AN XY: 74392

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.889

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.667

Gnomad4 SAS AF: 0.921

Gnomad4 FIN AF: 0.777

Gnomad4 NFE AF: 0.817

Gnomad4 OTH AF: 0.841

Alfa AF: 0.824 Hom.: 131766

Bravo AF: 0.836

TwinsUK AF: 0.816 AC: 3025

ALSPAC AF: 0.810 AC: 3120

ESP6500AA AF: 0.846 AC: 3728

ESP6500EA AF: 0.824 AC: 7087

ExAC AF: 0.833 AC: 101114

Asia WGS AF: 0.768 AC: 2670 AN: 3478

EpiCase AF: 0.835

EpiControl AF: 0.831

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	0.054
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0000015	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0000039	P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.0	N;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.56	T;.;.;.
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.0030	B;.;.;.
Vest4		0.27
MPC		1.0
ClinPred		0.025	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1950902; hg19: chr14-64882380; COSMIC: COSV53699778; COSMIC: COSV53699778;