NM_006636.4:c.563-348A>G

Variant names:

• chr2-74209594-A-G
• rs828903
• NM_006636.4:c.563-348A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	NM_006636.4	MANE Select	c.563-348A>G		intron	N/A	NP_006627.2
	MTHFD2	NM_001410192.1		c.257-348A>G		intron	N/A	NP_001397121.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	ENST00000394053.7	TSL:1 MANE Select	c.563-348A>G		intron	N/A	ENSP00000377617.2
	MTHFD2	ENST00000677299.1		n.576A>G		non_coding_transcript_exon	Exon 1 of 4
	MTHFD2	ENST00000677997.1		c.485-348A>G		intron	N/A	ENSP00000503074.1

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

African (AFR) AF: 0.659 AC: 27165 AN: 41252

American (AMR) AF: 0.398 AC: 6047 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1450 AN: 3470

East Asian (EAS) AF: 0.238 AC: 1216 AN: 5108

South Asian (SAS) AF: 0.237 AC: 1136 AN: 4792

European-Finnish (FIN) AF: 0.550 AC: 5739 AN: 10426

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30707 AN: 67868

Other (OTH) AF: 0.479 AC: 1008 AN: 2106

Alfa AF: 0.450 Hom.: 10977

Bravo AF: 0.492

Asia WGS AF: 0.291 AC: 1013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.31
DANN	Benign	0.21
PhyloP100		-2.0
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: rs828903; hg19: chr2-74436721;