rs17037388

Variant names:

• chr1-11797979-A-G
• rs17037388
• NM_005957.5:c.587-1580T>C

Variant summary

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

The NM_005957.5(MTHFR):​c.587-1580T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,176 control chromosomes in the GnomAD database, including 2,433 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 0.17 (2433 hom., cov: 33)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391
• Publications: 16 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 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.587-1580T>C		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.710-1580T>C		intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.707-1580T>C		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.587-1580T>C		intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.707-1580T>C		intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.587-1580T>C		intron	N/A	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26136 AN: 152058 Hom.: 2433 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.157

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

GnomAD4 genome AF: 0.172 AC: 26162 AN: 152176 Hom.: 2433 Cov.: 33 AF XY: 0.172 AC XY: 12826 AN XY: 74382

African (AFR) AF: 0.225 AC: 9318 AN: 41494

American (AMR) AF: 0.123 AC: 1880 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3472

East Asian (EAS) AF: 0.129 AC: 666 AN: 5172

South Asian (SAS) AF: 0.203 AC: 980 AN: 4820

European-Finnish (FIN) AF: 0.159 AC: 1691 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10814 AN: 68006

Other (OTH) AF: 0.156 AC: 330 AN: 2112

Alfa AF: 0.158 Hom.: 1146

Bravo AF: 0.168

Asia WGS AF: 0.168 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.77
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17037388; hg19: chr1-11858036;