rs2236222

Positions:

• chr14-64448464-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000258824 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2279+147A>G		intron_variant		ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2279+147A>G		intron_variant			NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2279+147A>G		intron_variant			NM_005956.4	ENSP00000498336.1

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

Gnomad4 AFR exome AF: 0.0554

Gnomad4 AMR exome AF: 0.0641

Gnomad4 ASJ exome AF: 0.0843

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0802

Gnomad4 NFE exome AF: 0.0856

Gnomad4 OTH exome AF: 0.0884

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

Gnomad4 AFR AF: 0.0574

Gnomad4 AMR AF: 0.0629

Gnomad4 ASJ AF: 0.0838

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.0785

Gnomad4 NFE AF: 0.0871

Gnomad4 OTH AF: 0.0756

Alfa AF: 0.0826 Hom.: 151

Bravo AF: 0.0778

Asia WGS AF: 0.138 AC: 477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.018
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs2236222; hg19: chr14-64915182; COSMIC: COSV53698939; COSMIC: COSV53698939;