rs1537515

Positions:

• chr1-11787845-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005957.5(MTHFR):​c.*2835G>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 0.108 in 1,201,058 control chromosomes in the GnomAD database, including 7,408 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 0.097 (782 hom., cov: 33)
  • Exomes 𝑓: 0.11 (6626 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397

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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.*2835G>T		3_prime_UTR_variant	12/12	ENST00000376590.9	NP_005948.3
C1orf167	NM_001010881.2	c.3674-28C>A		intron_variant		ENST00000688073.1	NP_001010881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.*2835G>T		3_prime_UTR_variant	12/12	1	NM_005957.5	ENSP00000365775	A1
C1orf167	ENST00000688073.1	c.3674-28C>A		intron_variant			NM_001010881.2	ENSP00000510540	A2

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14729 AN: 152110 Hom.: 780 Cov.: 33

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0808

GnomAD3 exomes AF: 0.103 AC: 8299 AN: 80722 Hom.: 497 AF XY: 0.105 AC XY: 4233 AN XY: 40500

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.0661

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0911

GnomAD4 exome AF: 0.109 AC: 114428 AN: 1048830 Hom.: 6626 Cov.: 30 AF XY: 0.111 AC XY: 55726 AN XY: 502702

Gnomad4 AFR exome AF: 0.0728

Gnomad4 AMR exome AF: 0.0665

Gnomad4 ASJ exome AF: 0.0351

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0969 AC: 14750 AN: 152228 Hom.: 782 Cov.: 33 AF XY: 0.0983 AC XY: 7313 AN XY: 74416

Gnomad4 AFR AF: 0.0813

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0809

Alfa AF: 0.0868 Hom.: 145

Bravo AF: 0.0877

Asia WGS AF: 0.146 AC: 509 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1537515; hg19: chr1-11847902;