rs12121543

Variant names:

• chr1-11794614-C-A
• rs12121543
• NM_005957.5:c.1167-76G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.1167-76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,607,144 control chromosomes in the GnomAD database, including 48,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3722 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45065 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.137
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-11794614-C-A is Benign according to our data. Variant chr1-11794614-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1177041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.323 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.1167-76G>T		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.1290-76G>T		intron	N/A	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1287-76G>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.1167-76G>T		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1287-76G>T		intron	N/A	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1167-76G>T		intron	N/A	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32419 AN: 151922 Hom.: 3726 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.245 AC: 356202 AN: 1455104 Hom.: 45065 Cov.: 34 AF XY: 0.249 AC XY: 180016 AN XY: 724260

African (AFR) AF: 0.134 AC: 4460 AN: 33354

American (AMR) AF: 0.132 AC: 5906 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5880 AN: 26082

East Asian (EAS) AF: 0.194 AC: 7694 AN: 39632

South Asian (SAS) AF: 0.345 AC: 29694 AN: 86028

European-Finnish (FIN) AF: 0.272 AC: 14475 AN: 53170

Middle Eastern (MID) AF: 0.254 AC: 1464 AN: 5758

European-Non Finnish (NFE) AF: 0.246 AC: 272017 AN: 1106204

Other (OTH) AF: 0.243 AC: 14612 AN: 60164

GnomAD4 genome AF: 0.213 AC: 32433 AN: 152040 Hom.: 3722 Cov.: 32 AF XY: 0.215 AC XY: 15992 AN XY: 74294

African (AFR) AF: 0.144 AC: 5955 AN: 41492

American (AMR) AF: 0.156 AC: 2386 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 782 AN: 3468

East Asian (EAS) AF: 0.208 AC: 1069 AN: 5146

South Asian (SAS) AF: 0.337 AC: 1625 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3029 AN: 10568

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16894 AN: 67954

Other (OTH) AF: 0.216 AC: 456 AN: 2110

Alfa AF: 0.229 Hom.: 6604

Bravo AF: 0.197

Asia WGS AF: 0.257 AC: 893 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.75
PhyloP100		-0.14
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12121543; hg19: chr1-11854671; COSMIC: COSV64877122; COSMIC: COSV64877122;