rs3753584

Variant names:

• chr1-11804529-T-C
• rs3753584
• ENST00000376592.6:c.-1413A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376592.6. 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
	MTHFR	NM_005957.5	MANE Select	c.-14+1359A>G		intron	N/A	NP_005948.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376592.6	TSL:1	c.-1413A>G		5_prime_UTR	Exon 2 of 12	ENSP00000365777.1	P42898-1
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.-14+1359A>G		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376486.3	TSL:1	c.-11+1359A>G		intron	N/A	ENSP00000365669.3	F8W9T8

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

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) AF: 0.0625 AC: 1 AN: 16

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.136 AC: 6 AN: 44

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.129 AC: 5308 AN: 41082

American (AMR) AF: 0.110 AC: 1661 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 298 AN: 3460

East Asian (EAS) AF: 0.126 AC: 652 AN: 5156

South Asian (SAS) AF: 0.201 AC: 961 AN: 4778

European-Finnish (FIN) AF: 0.166 AC: 1655 AN: 9974

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10622 AN: 67776

Other (OTH) AF: 0.133 AC: 277 AN: 2090

Alfa AF: 0.144 Hom.: 2186

Bravo AF: 0.136

Asia WGS AF: 0.162 AC: 562 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		0.32
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3753584; hg19: chr1-11864586;