1-11797894-T-C

Variant names:

• chr1-11797894-T-C
• rs4846052
• NM_005957.5:c.587-1495A>G

Variant summary

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

The NM_005957.5(MTHFR):​c.587-1495A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,056 control chromosomes in the GnomAD database, including 21,329 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 0.49 (21329 hom., cov: 32)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• Publications: 35 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. 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.587-1495A>G		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.710-1495A>G		intron	N/A	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.707-1495A>G		intron	N/A	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.587-1495A>G		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.707-1495A>G		intron	N/A	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.587-1495A>G		intron	N/A	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75037 AN: 151938 Hom.: 21328 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.515

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.494 AC: 75052 AN: 152056 Hom.: 21329 Cov.: 32 AF XY: 0.499 AC XY: 37046 AN XY: 74294

African (AFR) AF: 0.198 AC: 8220 AN: 41492

American (AMR) AF: 0.659 AC: 10061 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2120 AN: 3470

East Asian (EAS) AF: 0.771 AC: 3979 AN: 5160

South Asian (SAS) AF: 0.474 AC: 2276 AN: 4804

European-Finnish (FIN) AF: 0.631 AC: 6661 AN: 10564

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39949 AN: 67980

Other (OTH) AF: 0.515 AC: 1088 AN: 2114

Alfa AF: 0.567 Hom.: 41434

Bravo AF: 0.486

Asia WGS AF: 0.597 AC: 2077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.38
DANN	Benign	0.51
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4846052; hg19: chr1-11857951;