rs12196

chr2-74214672-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.930

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 Benign. Variant got -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	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2	NM_006636.4	c.*430A>G		3_prime_UTR_variant	8/8	ENST00000394053.7
MTHFD2	NM_001410192.1	c.*430A>G		3_prime_UTR_variant	9/9
MTHFD2	XM_006711924.3	c.*430A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2	ENST00000394053.7	c.*430A>G		3_prime_UTR_variant	8/8	1	NM_006636.4	P1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57197 AN: 151992 Hom.: 11281 Cov.: 33

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.: 62 Cov.: 0 AF XY: 0.410 AC XY: 133 AN XY: 324

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.376 AC: 57220 AN: 152110 Hom.: 11286 Cov.: 33 AF XY: 0.376 AC XY: 27967 AN XY: 74356

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.385

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	12
Dann	Benign	0.91

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: rs12196; hg19: chr2-74441799;