1-11786195-G-A

Variant names:

• chr1-11786195-G-A
• rs4846048
• NM_005957.5:c.*4485C>T

Variant summary

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

The NM_005957.5(MTHFR):​c.*4485C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 152,126 control chromosomes in the GnomAD database, including 35,720 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 0.68 (35706 hom., cov: 32)
  • Exomes 𝑓: 0.72 (14 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.476
• Publications: 70 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.874 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.*4485C>T		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3567+906G>A		intron	N/A	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_001330358.2		c.*4485C>T		3_prime_UTR	Exon 12 of 12	NP_001317287.1	P42898-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*4485C>T		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376592.6	TSL:1	c.*4485C>T		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
	C1orf167	ENST00000688073.1	MANE Select	c.3567+906G>A		intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103021 AN: 151956 Hom.: 35684 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.667

GnomAD4 exome AF: 0.722 AC: 39 AN: 54 Hom.: 14 Cov.: 0 AF XY: 0.806 AC XY: 29 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.750 AC: 3 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.900 AC: 9 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.656 AC: 21 AN: 32

Other (OTH) AF: 0.750 AC: 6 AN: 8

GnomAD4 genome AF: 0.678 AC: 103094 AN: 152072 Hom.: 35706 Cov.: 32 AF XY: 0.683 AC XY: 50781 AN XY: 74360

African (AFR) AF: 0.545 AC: 22594 AN: 41452

American (AMR) AF: 0.776 AC: 11863 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2327 AN: 3468

East Asian (EAS) AF: 0.895 AC: 4641 AN: 5184

South Asian (SAS) AF: 0.668 AC: 3226 AN: 4828

European-Finnish (FIN) AF: 0.783 AC: 8278 AN: 10576

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47997 AN: 67972

Other (OTH) AF: 0.665 AC: 1403 AN: 2110

Alfa AF: 0.693 Hom.: 124601

Bravo AF: 0.671

Asia WGS AF: 0.753 AC: 2617 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	1.7
DANN	Benign	0.49
PhyloP100		0.48
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: rs4846048; hg19: chr1-11846252;