2-74211279-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006636.4(MTHFD2):c.751A>G(p.Ile251Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,599,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: MTHFD2 NM_006636.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.01

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012758344).
• BP6: Variant 2-74211279-A-G is Benign according to our data. Variant chr2-74211279-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2212770.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2	NM_006636.4	c.751A>G	p.Ile251Val	missense_variant	6/8	ENST00000394053.7
MTHFD2	NM_001410192.1	c.445A>G	p.Ile149Val	missense_variant	7/9
MTHFD2	XM_006711924.3	c.445A>G	p.Ile149Val	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2	ENST00000394053.7	c.751A>G	p.Ile251Val	missense_variant	6/8	1	NM_006636.4	P1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000928 AC: 23 AN: 247882 Hom.: 0 AF XY: 0.0000669 AC XY: 9 AN XY: 134532

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000470 AC: 68 AN: 1447570 Hom.: 0 Cov.: 26 AF XY: 0.0000444 AC XY: 32 AN XY: 721034

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000182

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27 AN XY: 74492

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000536

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.7
Dann	Benign	0.80
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.78	T;T;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.22
MVP		0.27
MPC		0.12
ClinPred		0.0046	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs183389698; hg19: chr2-74438406;