14-64421337-C-T

Variant names:

• chr14-64421337-C-T
• rs1885031
• NM_005956.4:c.727+1412C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005956.4(MTHFD1):​c.727+1412C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 152,270 control chromosomes in the GnomAD database, including 63,527 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.91 (63527 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.966 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	NM_005956.4	MANE Select	c.727+1412C>T		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.727+1412C>T		intron	N/A	NP_001351766.1	F5H2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.727+1412C>T		intron	N/A	ENSP00000498336.1	P11586
	MTHFD1	ENST00000555252.5	TSL:1	n.784+1412C>T		intron	N/A
	MTHFD1	ENST00000545908.6	TSL:2	c.727+1412C>T		intron	N/A	ENSP00000438588.2	F5H2F4

Frequencies

GnomAD3 genomes AF: 0.911 AC: 138649 AN: 152152 Hom.: 63475 Cov.: 32

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.901

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.911 AC: 138759 AN: 152270 Hom.: 63527 Cov.: 32 AF XY: 0.909 AC XY: 67675 AN XY: 74446

African (AFR) AF: 0.974 AC: 40482 AN: 41576

American (AMR) AF: 0.870 AC: 13314 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3158 AN: 3472

East Asian (EAS) AF: 0.663 AC: 3423 AN: 5162

South Asian (SAS) AF: 0.957 AC: 4618 AN: 4828

European-Finnish (FIN) AF: 0.885 AC: 9370 AN: 10592

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61349 AN: 68024

Other (OTH) AF: 0.902 AC: 1906 AN: 2114

Alfa AF: 0.908 Hom.: 26742

Bravo AF: 0.908

Asia WGS AF: 0.838 AC: 2917 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.45
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1885031; hg19: chr14-64888055;