rs3818239

Variant names:

• chr14-64447819-T-C
• rs3818239
• NM_005956.4:c.2179-398T>C

Variant summary

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

The NM_005956.4(MTHFD1):​c.2179-398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,136 control chromosomes in the GnomAD database, including 2,128 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 0.15 (2128 hom., cov: 31)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• Publications: 20 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)

ENSG00000258824 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2179-398T>C		intron_variant	Intron 22 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2179-398T>C		intron_variant	Intron 22 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2179-398T>C		intron_variant	Intron 22 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23316 AN: 152018 Hom.: 2124 Cov.: 31

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.0977

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.153 AC: 23341 AN: 152136 Hom.: 2128 Cov.: 31 AF XY: 0.150 AC XY: 11191 AN XY: 74368

African (AFR) AF: 0.258 AC: 10684 AN: 41442

American (AMR) AF: 0.0997 AC: 1524 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0977 AC: 339 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1179 AN: 5178

South Asian (SAS) AF: 0.0578 AC: 279 AN: 4824

European-Finnish (FIN) AF: 0.0974 AC: 1032 AN: 10596

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7849 AN: 68016

Other (OTH) AF: 0.139 AC: 294 AN: 2116

Alfa AF: 0.121 Hom.: 2106

Bravo AF: 0.158

Asia WGS AF: 0.156 AC: 539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.4
DANN	Benign	0.74
PhyloP100		-0.13
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: rs3818239; hg19: chr14-64914537;