NM_005956.4:c.2137-617G>A

Variant names:

• chr14-64444076-G-A
• rs1256142
• NM_005956.4:c.2137-617G>A

Variant summary

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

The NM_005956.4(MTHFD1):​c.2137-617G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 149,986 control chromosomes in the GnomAD database, including 25,431 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 0.57 (25431 hom., cov: 24)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• 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)

ENSG00000258824 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2137-617G>A		intron_variant	Intron 21 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2137-617G>A		intron_variant	Intron 21 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2137-617G>A		intron_variant	Intron 21 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 85572 AN: 149868 Hom.: 25410 Cov.: 24

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.571 AC: 85646 AN: 149986 Hom.: 25431 Cov.: 24 AF XY: 0.562 AC XY: 41108 AN XY: 73148

African (AFR) AF: 0.734 AC: 29861 AN: 40656

American (AMR) AF: 0.459 AC: 6929 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1927 AN: 3460

East Asian (EAS) AF: 0.533 AC: 2692 AN: 5054

South Asian (SAS) AF: 0.467 AC: 2192 AN: 4690

European-Finnish (FIN) AF: 0.421 AC: 4327 AN: 10272

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.533 AC: 35944 AN: 67480

Other (OTH) AF: 0.575 AC: 1197 AN: 2080

Alfa AF: 0.553 Hom.: 8559

Bravo AF: 0.584

Asia WGS AF: 0.493 AC: 1715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.56
PhyloP100		0.54
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: rs1256142; hg19: chr14-64910794;