NM_006636.4:c.74T>C

Variant names:

• chr2-74198715-T-C
• rs942176205
• NM_006636.4:c.74T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006636.4(MTHFD2):​c.74T>C​(p.Leu25Pro) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTHFD2 NM_006636.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38
• 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]

ENSG00000279070 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07749984).
• BP6: Variant 2-74198715-T-C is Benign according to our data. Variant chr2-74198715-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3215258.Status of the report is criteria_provided_single_submitter, 1 stars.

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.74T>C	p.Leu25Pro	missense	Exon 1 of 8	NP_006627.2	P13995-1
	MTHFD2	NM_001410192.1		c.-331T>C		5_prime_UTR	Exon 1 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.74T>C	p.Leu25Pro	missense	Exon 1 of 8	ENSP00000377617.2	P13995-1
	MTHFD2	ENST00000409601.1	TSL:5	c.74T>C	p.Leu25Pro	missense	Exon 1 of 6	ENSP00000386542.1	B8ZZU9
	MTHFD2	ENST00000409804.5	TSL:5	c.74T>C	p.Leu25Pro	missense	Exon 1 of 5	ENSP00000386536.1	B9A062

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.063
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.082
DANN	Benign	0.42
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.049
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.61		Loss of stability (P = 0.0049)
MVP		0.13
MPC		0.24
ClinPred		0.078	T
GERP RS		-4.2
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.23
Mutation Taster		=287/13	polymorphism

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: rs942176205; hg19: chr2-74425842;