Genetic Variant MTHFD2:p.Arg54Gln (chr2-74205764-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006636.4(MTHFD2):c.161G>A(p.Arg54Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MTHFD2
NM_006636.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92

Variant links:

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]

MTHFD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03999445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD2	NM_006636.4 link	c.161G>A	p.Arg54Gln	missense_variant	Exon 2 of 8	ENST00000394053.7	NP_006627.2	P13995-1
MTHFD2	NM_001410192.1 link	c.-146G>A		5_prime_UTR_variant	Exon 3 of 9		NP_001397121.1
MTHFD2	XM_006711924.3 link	c.-20-1940G>A		intron_variant	Intron 1 of 6		XP_006711987.1	P13995-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7 link	c.161G>A	p.Arg54Gln	missense_variant	Exon 2 of 8	1	NM_006636.4	ENSP00000377617.2		P13995-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249502

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

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:

0.00000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161G>A (p.R54Q) alteration is located in exon 2 (coding exon 2) of the MTHFD2 gene. This alteration results from a G to A substitution at nucleotide position 161, causing the arginine (R) at amino acid position 54 to be replaced by a glutamine (Q). 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

Benign

0.070

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.31

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

D;T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.085

N;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.39

T;D;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.025

B;.;B

Vest4

0.17

MVP

0.39

MPC

0.17

ClinPred

0.056

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over