14-64415662-A-G

Variant names:

• chr14-64415662-A-G
• rs1950902
• NM_005956.4:c.401A>G

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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:5
• Conservation: PhyloP100: 8.82
• Publications: 127 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	NM_005956.4	MANE Select	c.401A>G	p.Lys134Arg	missense	Exon 6 of 28	NP_005947.3
	MTHFD1	NM_001364837.1		c.401A>G	p.Lys134Arg	missense	Exon 6 of 27	NP_001351766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.401A>G	p.Lys134Arg	missense	Exon 6 of 28	ENSP00000498336.1
	MTHFD1	ENST00000555252.5	TSL:1	n.458A>G		non_coding_transcript_exon	Exon 5 of 17
	MTHFD1	ENST00000545908.6	TSL:2	c.401A>G	p.Lys134Arg	missense	Exon 6 of 27	ENSP00000438588.2

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

GnomAD2 exomes AF: 0.835 AC: 208038 AN: 249270 AF XY: 0.838

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 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

African (AFR) AF: 0.849 AC: 28404 AN: 33446

American (AMR) AF: 0.908 AC: 40603 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 21916 AN: 26124

East Asian (EAS) AF: 0.735 AC: 29173 AN: 39690

South Asian (SAS) AF: 0.924 AC: 79649 AN: 86234

European-Finnish (FIN) AF: 0.785 AC: 41899 AN: 53400

Middle Eastern (MID) AF: 0.911 AC: 5251 AN: 5766

European-Non Finnish (NFE) AF: 0.814 AC: 904035 AN: 1110830

Other (OTH) AF: 0.821 AC: 49569 AN: 60352

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

African (AFR) AF: 0.846 AC: 35138 AN: 41522

American (AMR) AF: 0.889 AC: 13588 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 2937 AN: 3472

East Asian (EAS) AF: 0.667 AC: 3436 AN: 5152

South Asian (SAS) AF: 0.921 AC: 4442 AN: 4824

European-Finnish (FIN) AF: 0.777 AC: 8229 AN: 10588

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55595 AN: 68008

Other (OTH) AF: 0.841 AC: 1780 AN: 2116

Alfa AF: 0.823 Hom.: 263358

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 03, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
PhyloP100		8.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.24
Sift	Benign	0.56	T
Sift4G	Benign	0.64	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
Mutation Taster		=82/18	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1950902; hg19: chr14-64882380; COSMIC: COSV53699778; COSMIC: COSV53699778;