rs17421511

Variant names:

• chr1-11797731-G-A
• rs17421511
• NM_005957.5:c.587-1332C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005957.5(MTHFR):​c.587-1332C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,206 control chromosomes in the GnomAD database, including 1,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1487 hom., cov: 32)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.216
• Publications: 42 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-11797731-G-A is Benign according to our data. Variant chr1-11797731-G-A is described in ClinVar as Benign. ClinVar VariationId is 1168301.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 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.587-1332C>T		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.710-1332C>T		intron	N/A	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.707-1332C>T		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.587-1332C>T		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.707-1332C>T		intron	N/A	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.587-1332C>T		intron	N/A	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19367 AN: 152088 Hom.: 1489 Cov.: 32

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.148

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

GnomAD4 genome AF: 0.127 AC: 19365 AN: 152206 Hom.: 1487 Cov.: 32 AF XY: 0.128 AC XY: 9515 AN XY: 74410

African (AFR) AF: 0.0439 AC: 1824 AN: 41548

American (AMR) AF: 0.103 AC: 1571 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3472

East Asian (EAS) AF: 0.0980 AC: 508 AN: 5184

South Asian (SAS) AF: 0.207 AC: 1001 AN: 4832

European-Finnish (FIN) AF: 0.169 AC: 1790 AN: 10576

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11383 AN: 68002

Other (OTH) AF: 0.148 AC: 312 AN: 2112

Alfa AF: 0.156 Hom.: 2951

Bravo AF: 0.118

Asia WGS AF: 0.152 AC: 530 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.60
PhyloP100		0.22
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: rs17421511; hg19: chr1-11857788; COSMIC: COSV64877190; COSMIC: COSV64877190;