rs828858

Positions:

• chr2-74195067-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000677997.1(MTHFD2):​c.23+7610T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 152,030 control chromosomes in the GnomAD database, including 9,212 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 0.33 (9212 hom., cov: 30)
• Consequence: MTHFD2 ENST00000677997.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650

Genes affected

MTHFD2 (HGNC:7434): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase) This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The enzyme functions as a homodimer and is unique in its absolute requirement for magnesium and inorganic phosphate. Formation of the enzyme-magnesium complex allows binding of NAD. Alternative splicing results in two different transcripts, one protein-coding and the other not protein-coding. This gene has a pseudogene on chromosome 7. [provided by RefSeq, Mar 2009]

(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 (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.74195067T>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000677997.1	c.23+7610T>A		intron_variant				ENSP00000503074.1
MTHFD2	ENST00000677170.1	c.-303-6315T>A		intron_variant				ENSP00000503486.1
MTHFD2	ENST00000678684.1	c.-206+7947T>A		intron_variant				ENSP00000504687.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49823 AN: 151912 Hom.: 9208 Cov.: 30

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.328 AC: 49835 AN: 152030 Hom.: 9212 Cov.: 30 AF XY: 0.329 AC XY: 24415 AN XY: 74312

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.351

Alfa AF: 0.377 Hom.: 1434

Bravo AF: 0.299

Asia WGS AF: 0.186 AC: 649 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	4.7
DANN	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs828858; hg19: chr2-74422194;