chr2-74215304-T-G

Variant names:

• chr2-74215304-T-G
• rs828853
• NM_006636.4:c.*1062T>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.*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
• Publications: 9 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 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.*1062T>G		3_prime_UTR	Exon 8 of 8	NP_006627.2
	MTHFD2	NM_001410192.1		c.*1062T>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.*1062T>G		3_prime_UTR	Exon 8 of 8	ENSP00000377617.2
	ENSG00000264324	ENST00000451608.2	TSL:5	n.*4185+779A>C		intron	N/A	ENSP00000416453.2
	MTHFD2	ENST00000489041.2	TSL:2	n.*2096T>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000419550.2

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.563 AC: 126 AN: 224

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		-0.19
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: rs828853; hg19: chr2-74442431;