2-74211259-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006636.4(MTHFD2):c.731C>T(p.Thr244Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T244K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MTHFD2 NM_006636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2	NM_006636.4	c.731C>T	p.Thr244Ile	missense_variant	6/8	ENST00000394053.7
MTHFD2	NM_001410192.1	c.425C>T	p.Thr142Ile	missense_variant	7/9
MTHFD2	XM_006711924.3	c.425C>T	p.Thr142Ile	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2	ENST00000394053.7	c.731C>T	p.Thr244Ile	missense_variant	6/8	1	NM_006636.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455278 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.731C>T (p.T244I) alteration is located in exon 6 (coding exon 6) of the MTHFD2 gene. This alteration results from a C to T substitution at nucleotide position 731, causing the threonine (T) at amino acid position 244 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.23
Sift	Benign	0.037	D;D;D
Sift4G	Benign	0.14	T;D;T
Polyphen		0.12	B;.;B
Vest4		0.92
MutPred		0.64		Gain of methylation at K242 (P = 0.0758);.;.;
MVP		0.72
MPC		0.23
ClinPred		0.91	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74438386;