NM_006636.4:c.101+3323C>T

Variant names:

• chr2-74202065-C-T
• rs1667627
• NM_006636.4:c.101+3323C>T

Variant summary

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

The NM_006636.4(MTHFD2):​c.101+3323C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,692 control chromosomes in the GnomAD database, including 30,148 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 0.62 (30148 hom., cov: 30)
• Consequence: MTHFD2 NM_006636.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• Publications: 17 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD2	NM_006636.4	c.101+3323C>T		intron_variant	Intron 1 of 7	ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1	c.-206+586C>T		intron_variant	Intron 2 of 8		NP_001397121.1
MTHFD2	XM_006711924.3	c.-21+3323C>T		intron_variant	Intron 1 of 6		XP_006711987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7	c.101+3323C>T		intron_variant	Intron 1 of 7	1	NM_006636.4	ENSP00000377617.2

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93681 AN: 151578 Hom.: 30091 Cov.: 30

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.593

Gnomad NFE AF: 0.535

Gnomad OTH AF: 0.598

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

GnomAD4 genome AF: 0.618 AC: 93793 AN: 151692 Hom.: 30148 Cov.: 30 AF XY: 0.617 AC XY: 45727 AN XY: 74072

African (AFR) AF: 0.802 AC: 33210 AN: 41414

American (AMR) AF: 0.608 AC: 9258 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1792 AN: 3468

East Asian (EAS) AF: 0.604 AC: 3119 AN: 5160

South Asian (SAS) AF: 0.375 AC: 1803 AN: 4808

European-Finnish (FIN) AF: 0.615 AC: 6413 AN: 10426

Middle Eastern (MID) AF: 0.597 AC: 172 AN: 288

European-Non Finnish (NFE) AF: 0.535 AC: 36319 AN: 67906

Other (OTH) AF: 0.600 AC: 1258 AN: 2096

Alfa AF: 0.563 Hom.: 10309

Bravo AF: 0.632

Asia WGS AF: 0.515 AC: 1791 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.74
PhyloP100		-0.036
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: rs1667627; hg19: chr2-74429192;