rs4846048

Positions:

• chr1-11786195-G-A
• chr1-11786195-G-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.*4485C>T		3_prime_UTR_variant	12/12	ENST00000376590.9	NP_005948.3
C1orf167	NM_001010881.2	c.3567+906G>A		intron_variant		ENST00000688073.1	NP_001010881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590	c.*4485C>T		3_prime_UTR_variant	12/12	1	NM_005957.5	ENSP00000365775.3
C1orf167	ENST00000688073.1	c.3567+906G>A		intron_variant			NM_001010881.2	ENSP00000510540.1

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

Gnomad4 EAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.900

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.750

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

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.895

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.783

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.665

Alfa AF: 0.699 Hom.: 76816

Bravo AF: 0.671

Asia WGS AF: 0.753 AC: 2617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs4846048; hg19: chr1-11846252;