2-74214228-G-T

Variant names:

• chr2-74214228-G-T
• rs373797950
• NM_006636.4:c.1039G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006636.4(MTHFD2):​c.1039G>T​(p.Val347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: MTHFD2 NM_006636.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81

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]

ENSG00000264324 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD2	NM_006636.4	c.1039G>T	p.Val347Leu	missense_variant	Exon 8 of 8	ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1	c.733G>T	p.Val245Leu	missense_variant	Exon 9 of 9		NP_001397121.1
MTHFD2	XM_006711924.3	c.733G>T	p.Val245Leu	missense_variant	Exon 7 of 7		XP_006711987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7	c.1039G>T	p.Val347Leu	missense_variant	Exon 8 of 8	1	NM_006636.4	ENSP00000377617.2
ENSG00000264324	ENST00000451608.2	n.*4259+174C>A		intron_variant	Intron 38 of 38	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.43	B;.;B
Vest4		0.074
MutPred		0.16		Loss of methylation at K343 (P = 0.0829);.;.;
MVP		0.50
MPC		0.16
ClinPred		0.60	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs373797950; hg19: chr2-74441355;