rs3753582

Positions:

• chr1-11805485-A-C

Variant summary

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

The NM_005957.5(MTHFR):​c.-14+403T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 152,342 control chromosomes in the GnomAD database, including 794 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 (794 hom., cov: 33)
  • Exomes 𝑓: 0.069 (0 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203

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]

MTHFR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.-14+403T>G		intron_variant		ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.-14+403T>G		intron_variant		1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14998 AN: 152166 Hom.: 797 Cov.: 33

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0823

GnomAD4 exome AF: 0.0690 AC: 4 AN: 58 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 4 AN XY: 48

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0952

GnomAD4 genome AF: 0.0985 AC: 14995 AN: 152284 Hom.: 794 Cov.: 33 AF XY: 0.0994 AC XY: 7402 AN XY: 74468

Gnomad4 AFR AF: 0.0946

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0824

Alfa AF: 0.0974 Hom.: 229

Bravo AF: 0.0921

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.1
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3753582; hg19: chr1-11865542;