rs2236222

Variant names:

• chr14-64448464-A-G
• rs2236222
• NM_005956.4:c.2279+147A>G

Variant summary

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

The NM_005956.4(MTHFD1):​c.2279+147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 715,754 control chromosomes in the GnomAD database, including 2,868 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 0.079 (541 hom., cov: 32)
  • Exomes 𝑓: 0.085 (2327 hom.)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.982
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 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.2279+147A>G		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.2279+147A>G		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.2279+147A>G		intron	N/A	ENSP00000498336.1	P11586
	MTHFD1	ENST00000545908.6	TSL:2	c.2279+147A>G		intron	N/A	ENSP00000438588.2	F5H2F4
	MTHFD1	ENST00000900031.1		c.2360+147A>G		intron	N/A	ENSP00000570090.1

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 12006 AN: 152096 Hom.: 541 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0871

Gnomad OTH AF: 0.0731

GnomAD4 exome AF: 0.0846 AC: 47654 AN: 563540 Hom.: 2327 Cov.: 6 AF XY: 0.0829 AC XY: 24992 AN XY: 301556

African (AFR) AF: 0.0554 AC: 873 AN: 15744

American (AMR) AF: 0.0641 AC: 2156 AN: 33612

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 1599 AN: 18966

East Asian (EAS) AF: 0.186 AC: 5818 AN: 31310

South Asian (SAS) AF: 0.0478 AC: 2872 AN: 60034

European-Finnish (FIN) AF: 0.0802 AC: 3144 AN: 39218

Middle Eastern (MID) AF: 0.0556 AC: 224 AN: 4032

European-Non Finnish (NFE) AF: 0.0856 AC: 28293 AN: 330362

Other (OTH) AF: 0.0884 AC: 2675 AN: 30262

GnomAD4 genome AF: 0.0789 AC: 12012 AN: 152214 Hom.: 541 Cov.: 32 AF XY: 0.0792 AC XY: 5896 AN XY: 74410

African (AFR) AF: 0.0574 AC: 2382 AN: 41534

American (AMR) AF: 0.0629 AC: 961 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 291 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1178 AN: 5164

South Asian (SAS) AF: 0.0410 AC: 198 AN: 4824

European-Finnish (FIN) AF: 0.0785 AC: 832 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0871 AC: 5923 AN: 68024

Other (OTH) AF: 0.0756 AC: 160 AN: 2116

Alfa AF: 0.0871 Hom.: 283

Bravo AF: 0.0778

Asia WGS AF: 0.138 AC: 477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.018
DANN	Benign	0.37
PhyloP100		-0.98
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: rs2236222; hg19: chr14-64915182; COSMIC: COSV53698939; COSMIC: COSV53698939;