chr2-74215304-T-G

Position:

• chr2-74215304-T-G

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190

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

Verdict is Benign. Variant got -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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD2	NM_006636.4	c.*1062T>G		3_prime_UTR_variant	8/8	ENST00000394053.7	NP_006627.2
MTHFD2	NM_001410192.1	c.*1062T>G		3_prime_UTR_variant	9/9		NP_001397121.1
MTHFD2	XM_006711924.3	c.*1062T>G		3_prime_UTR_variant	7/7		XP_006711987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000394053.7	c.*1062T>G		3_prime_UTR_variant	8/8	1	NM_006636.4	ENSP00000377617.2
ENSG00000264324	ENST00000451608.2	n.*4185+779A>C		intron_variant		5		ENSP00000416453.2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74414 AN: 151554 Hom.: 19181 Cov.: 33

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.: 38 Cov.: 0 AF XY: 0.588 AC XY: 87 AN XY: 148

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.491 AC: 74505 AN: 151672 Hom.: 19211 Cov.: 33 AF XY: 0.488 AC XY: 36194 AN XY: 74138

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.473

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	11
DANN	Benign	0.59

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: rs828853; hg19: chr2-74442431;