rs3753588

Variant names:

• chr1-11803847-C-T
• rs3753588
• ENST00000376592.6:c.-731G>A

Variant summary

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

The ENST00000376592.6(MTHFR):​c.-731G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 296,594 control chromosomes in the GnomAD database, including 1,558 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 0.098 (792 hom., cov: 32)
  • Exomes 𝑓: 0.099 (766 hom.)
• Consequence: MTHFR ENST00000376592.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.-13-718G>A		intron_variant	Intron 1 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.-13-718G>A		intron_variant	Intron 1 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14979 AN: 152056 Hom.: 795 Cov.: 32

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0821

GnomAD4 exome AF: 0.0993 AC: 14339 AN: 144420 Hom.: 766 Cov.: 0 AF XY: 0.101 AC XY: 7500 AN XY: 74614

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0653

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0988

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0977

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0984 AC: 14976 AN: 152174 Hom.: 792 Cov.: 32 AF XY: 0.0994 AC XY: 7391 AN XY: 74388

Gnomad4 AFR AF: 0.0945

Gnomad4 AMR AF: 0.0672

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0822

Alfa AF: 0.0970 Hom.: 104

Bravo AF: 0.0921

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.3
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3753588; hg19: chr1-11863904;