NM_005957.5:c.*3301A>G

Variant names:

• chr1-11787379-T-C
• rs2184226
• NM_005957.5:c.*3301A>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.*3301A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0788 in 1,281,526 control chromosomes in the GnomAD database, including 4,186 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 0.071 (428 hom., cov: 33)
  • Exomes 𝑓: 0.080 (3758 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Scores: Splicing: ADA: 0.0001432
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 28 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]

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0785 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.*3301A>G		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3568-9T>C		intron	N/A	NP_001010881.1
	MTHFR	NM_001330358.2		c.*3301A>G		3_prime_UTR	Exon 12 of 12	NP_001317287.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*3301A>G		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
	MTHFR	ENST00000376592.6	TSL:1	c.*3301A>G		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1
	C1orf167	ENST00000688073.1	MANE Select	c.3568-9T>C		intron	N/A	ENSP00000510540.1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10843 AN: 152168 Hom.: 427 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0871

GnomAD2 exomes AF: 0.0649 AC: 8824 AN: 135982 AF XY: 0.0683

Gnomad AFR exome AF: 0.0777

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.000403

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0755

GnomAD4 exome AF: 0.0799 AC: 90170 AN: 1129240 Hom.: 3758 Cov.: 29 AF XY: 0.0811 AC XY: 44763 AN XY: 552138

African (AFR) AF: 0.0854 AC: 2026 AN: 23724

American (AMR) AF: 0.0457 AC: 1152 AN: 25184

Ashkenazi Jewish (ASJ) AF: 0.0587 AC: 873 AN: 14866

East Asian (EAS) AF: 0.000245 AC: 3 AN: 12238

South Asian (SAS) AF: 0.0940 AC: 6933 AN: 73780

European-Finnish (FIN) AF: 0.0357 AC: 915 AN: 25664

Middle Eastern (MID) AF: 0.126 AC: 529 AN: 4206

European-Non Finnish (NFE) AF: 0.0821 AC: 74608 AN: 909088

Other (OTH) AF: 0.0773 AC: 3131 AN: 40490

GnomAD4 genome AF: 0.0713 AC: 10856 AN: 152286 Hom.: 428 Cov.: 33 AF XY: 0.0694 AC XY: 5170 AN XY: 74478

African (AFR) AF: 0.0786 AC: 3268 AN: 41564

American (AMR) AF: 0.0577 AC: 882 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0825 AC: 398 AN: 4826

European-Finnish (FIN) AF: 0.0350 AC: 372 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0803 AC: 5461 AN: 68004

Other (OTH) AF: 0.0862 AC: 182 AN: 2112

Alfa AF: 0.0777 Hom.: 1094

Bravo AF: 0.0737

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.2
DANN	Benign	0.77
PhyloP100		-0.049
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.15		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: rs2184226; hg19: chr1-11847436; COSMIC: COSV57174939; COSMIC: COSV57174939;