2-74198320-G-T

Variant names:

• chr2-74198320-G-T
• rs56168672
• ENST00000677997.1:c.24-7385G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000677997.1(MTHFD2):​c.24-7385G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 145,460 control chromosomes in the GnomAD database, including 2,815 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 0.21 (1366 hom., cov: 21)
  • Exomes 𝑓: 0.25 (1449 hom.)
• Consequence: MTHFD2 ENST00000677997.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 1 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]

ENSG00000279070 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000677997.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	ENST00000677997.1		c.24-7385G>T		intron	N/A	ENSP00000503074.1
	MTHFD2	ENST00000677170.1		c.-303-3062G>T		intron	N/A	ENSP00000503486.1
	MTHFD2	ENST00000678684.1		c.-205-7385G>T		intron	N/A	ENSP00000504687.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 17091 AN: 80880 Hom.: 1362 Cov.: 21

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.247 AC: 15896 AN: 64468 Hom.: 1449 Cov.: 0 AF XY: 0.245 AC XY: 7958 AN XY: 32524

African (AFR) AF: 0.121 AC: 386 AN: 3202

American (AMR) AF: 0.395 AC: 1233 AN: 3122

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 585 AN: 2368

East Asian (EAS) AF: 0.430 AC: 3995 AN: 9296

South Asian (SAS) AF: 0.170 AC: 380 AN: 2234

European-Finnish (FIN) AF: 0.224 AC: 664 AN: 2960

Middle Eastern (MID) AF: 0.193 AC: 57 AN: 296

European-Non Finnish (NFE) AF: 0.206 AC: 7477 AN: 36294

Other (OTH) AF: 0.238 AC: 1119 AN: 4696

GnomAD4 genome AF: 0.211 AC: 17107 AN: 80992 Hom.: 1366 Cov.: 21 AF XY: 0.216 AC XY: 8551 AN XY: 39628

African (AFR) AF: 0.128 AC: 3696 AN: 28776

American (AMR) AF: 0.344 AC: 3428 AN: 9976

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 353 AN: 1512

East Asian (EAS) AF: 0.451 AC: 2018 AN: 4472

South Asian (SAS) AF: 0.196 AC: 674 AN: 3438

European-Finnish (FIN) AF: 0.231 AC: 716 AN: 3104

Middle Eastern (MID) AF: 0.196 AC: 20 AN: 102

European-Non Finnish (NFE) AF: 0.209 AC: 5880 AN: 28142

Other (OTH) AF: 0.235 AC: 252 AN: 1074

Alfa AF: 0.105 Hom.: 109

Bravo AF: 0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		0.51
PromoterAI		0.0089	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56168672; hg19: chr2-74425447;