2-74208674-T-C

Variant names:

• chr2-74208674-T-C
• NM_006636.4:c.515T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006636.4(MTHFD2):​c.515T>C​(p.Met172Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFD2 NM_006636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	NM_006636.4	MANE Select	c.515T>C	p.Met172Thr	missense	Exon 4 of 8	NP_006627.2	P13995-1
	MTHFD2	NM_001410192.1		c.209T>C	p.Met70Thr	missense	Exon 5 of 9	NP_001397121.1	P13995-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	ENST00000394053.7	TSL:1 MANE Select	c.515T>C	p.Met172Thr	missense	Exon 4 of 8	ENSP00000377617.2	P13995-1
	MTHFD2	ENST00000677997.1		c.437T>C	p.Met146Thr	missense	Exon 4 of 8	ENSP00000503074.1	A0A7I2V2U6
	MTHFD2	ENST00000409601.1	TSL:5	c.392T>C	p.Met131Thr	missense	Exon 3 of 6	ENSP00000386542.1	B8ZZU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.017	D
Sift4G	Benign	0.068	T
Polyphen		0.0010	B
Vest4		0.79
MutPred		0.73		Gain of glycosylation at S171 (P = 0.0515)
MVP		0.70
MPC		0.18
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.65
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr2-74435801;