chr2-74205764-G-T

Variant names:

• chr2-74205764-G-T
• NM_006636.4:c.161G>T

Variant summary

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

The NM_001410192.1(MTHFD2):​c.-146G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTHFD2 NM_001410192.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92

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 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.161G>T	p.Arg54Leu	missense_variant	Exon 2 of 8	ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1	c.-146G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 9		NP_001397121.1
MTHFD2	NM_001410192.1	c.-146G>T		5_prime_UTR_variant	Exon 3 of 9		NP_001397121.1
MTHFD2	XM_006711924.3	c.-20-1940G>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.161G>T	p.Arg54Leu	missense_variant	Exon 2 of 8	1	NM_006636.4	ENSP00000377617.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.0088
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.13
Sift	Benign	0.059	T;D;T
Sift4G	Benign	0.071	T;D;T
Polyphen		0.30	B;.;P
Vest4		0.58
MutPred		0.61		Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);
MVP		0.60
MPC		0.28
ClinPred		0.97	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.62

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: chr2-74432891;