Genetic Variant MTHFD2:c.*1062T>G (chr2-74215304-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006636.4(MTHFD2):c.*1062T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,672 control chromosomes in the GnomAD database, including 19,211 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19211 hom., cov: 33)

Exomes 𝑓: 0.56 ( 38 hom. )

Failed GnomAD Quality Control

Consequence

MTHFD2
NM_006636.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.190

Publications

9 publications found

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:

ENSG00000264324 (HGNC:):

ENSG00000264324 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
MTHFD2	NM_006636.4 link	c.*1062T>G	3_prime_UTR_variant	Exon 8 of 8	ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1 link	c.*1062T>G	3_prime_UTR_variant	Exon 9 of 9		NP_001397121.1
MTHFD2	XM_006711924.3 link	c.*1062T>G	3_prime_UTR_variant	Exon 7 of 7		XP_006711987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7 link	c.*1062T>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_006636.4	ENSP00000377617.2
ENSG00000264324	ENST00000451608.2 link	n.*4185+779A>C		intron_variant	Intron 37 of 38	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74414

AN:

151554

Hom.:

19181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.645

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.394

Gnomad ASJ

AF:

0.419

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.470

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.561

AC:

129

AN:

230

Hom.:

Cov.:

AF XY:

0.588

AC XY:

AN XY:

148

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.563

AC:

126

AN:

224

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.491

AC:

74505

AN:

151672

Hom.:

19211

Cov.:

AF XY:

0.488

AC XY:

36194

AN XY:

74138

show subpopulations

African (AFR)

AF:

0.645

AC:

26654

AN:

41328

American (AMR)

AF:

0.394

AC:

6005

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

1451

AN:

3466

East Asian (EAS)

AF:

0.239

AC:

1237

AN:

5176

South Asian (SAS)

AF:

0.238

AC:

1146

AN:

4822

European-Finnish (FIN)

AF:

0.550

AC:

5753

AN:

10452

Middle Eastern (MID)

AF:

0.527

AC:

154

AN:

292

European-Non Finnish (NFE)

AF:

0.453

AC:

30731

AN:

67864

Other (OTH)

AF:

0.473

AC:

997

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1895

3791

5686

7582

9477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

640

1280

1920

2560

3200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.477

Hom.:

2138

Bravo

AF:

0.489

Asia WGS

AF:

0.293

AC:

1019

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.59

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over