rs828903

Positions:

• chr2-74209594-A-G
• chr2-74209594-A-T

Variant summary

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

The NM_006636.4(MTHFD2):​c.563-348A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 151,428 control chromosomes in the GnomAD database, including 19,590 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 0.50 (19590 hom., cov: 29)
• Consequence: MTHFD2 NM_006636.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01

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]

MTHFD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD2	NM_006636.4	c.563-348A>G		intron_variant		ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1	c.257-348A>G		intron_variant			NP_001397121.1
MTHFD2	XM_006711924.3	c.257-348A>G		intron_variant			XP_006711987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7	c.563-348A>G		intron_variant		1	NM_006636.4	ENSP00000377617.2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 74920 AN: 151310 Hom.: 19563 Cov.: 29

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.495 AC: 75006 AN: 151428 Hom.: 19590 Cov.: 29 AF XY: 0.492 AC XY: 36387 AN XY: 73912

Gnomad4 AFR AF: 0.659

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.238

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.479

Alfa AF: 0.450 Hom.: 7478

Bravo AF: 0.492

Asia WGS AF: 0.291 AC: 1013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.31
DANN	Benign	0.21

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: rs828903; hg19: chr2-74436721;