chr2-74214672-A-G

Variant names:

• chr2-74214672-A-G
• rs12196
• NM_006636.4:c.*430A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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]

ENSG00000264324 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	NM_006636.4	MANE Select	c.*430A>G		3_prime_UTR	Exon 8 of 8	NP_006627.2
	MTHFD2	NM_001410192.1		c.*430A>G		3_prime_UTR	Exon 9 of 9	NP_001397121.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	ENST00000394053.7	TSL:1 MANE Select	c.*430A>G		3_prime_UTR	Exon 8 of 8	ENSP00000377617.2
	ENSG00000264324	ENST00000451608.2	TSL:5	n.*4186-197T>C		intron	N/A	ENSP00000416453.2
	MTHFD2	ENST00000470592.5	TSL:2	n.*1184A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000419067.1

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

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.517 AC: 207 AN: 400

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.225 AC: 32 AN: 142

Other (OTH) AF: 0.400 AC: 4 AN: 10

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12196; hg19: chr2-74441799;