rs3753584

Positions:

• chr1-11804529-T-C

Variant summary

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

The ENST00000376592.6(MTHFR):​c.-1413A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 150,732 control chromosomes in the GnomAD database, including 1,624 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 0.14 (1623 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: MTHFR ENST00000376592.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.-14+1359A>G		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.-14+1359A>G		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21540 AN: 150614 Hom.: 1624 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.121 AC: 8 AN: 66 Hom.: 1 Cov.: 0 AF XY: 0.100 AC XY: 5 AN XY: 50

Gnomad4 SAS exome AF: 0.0625

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.143 AC: 21548 AN: 150666 Hom.: 1623 Cov.: 32 AF XY: 0.144 AC XY: 10599 AN XY: 73488

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.133

Alfa AF: 0.145 Hom.: 1718

Bravo AF: 0.136

Asia WGS AF: 0.162 AC: 562 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	10
DANN	Benign	0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3753584; hg19: chr1-11864586;