dbSNP rs12196: MTHFD2:c.*430A>G (chr2-74214672-A-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.*430A>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 0.376 in 152,686 control chromosomes in the GnomAD database, including 11,348 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 0.38 ( 11286 hom., cov: 33)

Exomes 𝑓: 0.43 ( 62 hom. )

Consequence

MTHFD2
NM_006636.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.930

Publications

13 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=-0.63).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MTHFD2	NM_006636.4 link	c.*430A>G	3_prime_UTR_variant	Exon 8 of 8	ENST00000394053.7	NP_006627.2	P13995-1
MTHFD2	NM_001410192.1 link	c.*430A>G	3_prime_UTR_variant	Exon 9 of 9		NP_001397121.1
MTHFD2	XM_006711924.3 link	c.*430A>G	3_prime_UTR_variant	Exon 7 of 7		XP_006711987.1	P13995-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7 link	c.*430A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_006636.4	ENSP00000377617.2		P13995-1
ENSG00000264324	ENST00000451608.2 link	n.*4186-197T>C		intron_variant	Intron 37 of 38	5		ENSP00000416453.2		E7EWF7

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57197

AN:

151992

Hom.:

11281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.394

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.381

GnomAD4 exome

AF:

0.427

AC:

246

AN:

576

Hom.:

Cov.:

AF XY:

0.410

AC XY:

133

AN XY:

324

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.517

AC:

207

AN:

400

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.225

AC:

AN:

142

Other (OTH)

AF:

0.400

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.376

AC:

57220

AN:

152110

Hom.:

11286

Cov.:

AF XY:

0.376

AC XY:

27967

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.337

AC:

13965

AN:

41488

American (AMR)

AF:

0.282

AC:

4306

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1415

AN:

3468

East Asian (EAS)

AF:

0.142

AC:

737

AN:

5194

South Asian (SAS)

AF:

0.198

AC:

955

AN:

4830

European-Finnish (FIN)

AF:

0.529

AC:

5590

AN:

10562

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.426

AC:

28933

AN:

67966

Other (OTH)

AF:

0.385

AC:

815

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1819

3638

5457

7276

9095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.408

Hom.:

1612

Bravo

AF:

0.353

Asia WGS

AF:

0.209

AC:

727

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.93

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over