1-11801990-C-T

Variant names:

• chr1-11801990-C-T
• rs17037396
• NM_005957.5:c.237-591G>A

Variant summary

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

The NM_005957.5(MTHFR):​c.237-591G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 150,400 control chromosomes in the GnomAD database, including 795 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 0.099 (795 hom., cov: 31)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 23 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.237-591G>A		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.360-591G>A		intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.357-591G>A		intron	N/A	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.237-591G>A		intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.357-591G>A		intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.237-591G>A		intron	N/A	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.0990 AC: 14874 AN: 150306 Hom.: 798 Cov.: 31

Gnomad AFR AF: 0.0933

Gnomad AMI AF: 0.0475

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0324

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0390

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0832

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

GnomAD4 genome AF: 0.0989 AC: 14870 AN: 150400 Hom.: 795 Cov.: 31 AF XY: 0.0994 AC XY: 7288 AN XY: 73292

African (AFR) AF: 0.0931 AC: 3802 AN: 40842

American (AMR) AF: 0.0672 AC: 1017 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 112 AN: 3462

East Asian (EAS) AF: 0.131 AC: 678 AN: 5158

South Asian (SAS) AF: 0.156 AC: 745 AN: 4778

European-Finnish (FIN) AF: 0.123 AC: 1232 AN: 10024

Middle Eastern (MID) AF: 0.0451 AC: 13 AN: 288

European-Non Finnish (NFE) AF: 0.104 AC: 7055 AN: 67742

Other (OTH) AF: 0.0833 AC: 173 AN: 2076

Alfa AF: 0.0951 Hom.: 1049

Bravo AF: 0.0935

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.022
DANN	Benign	0.77
PhyloP100		-2.5
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: rs17037396; hg19: chr1-11862047;