rs41275468

Positions:

• chr1-11788086-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000376590.9(MTHFR):​c.*2594C>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 0.00394 in 1,280,862 control chromosomes in the GnomAD database, including 10 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 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (10 hom.)
• Consequence: MTHFR ENST00000376590.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (357/152378) while in subpopulation NFE AF= 0.00439 (299/68040). AF 95% confidence interval is 0.00398. There are 0 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.*2594C>T		3_prime_UTR_variant	12/12	ENST00000376590.9	NP_005948.3
C1orf167	NM_001010881.2	c.3848+39G>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.*2594C>T		3_prime_UTR_variant	12/12	1	NM_005957.5	ENSP00000365775	A1
C1orf167	ENST00000688073.1	c.3848+39G>A		intron_variant			NM_001010881.2	ENSP00000510540	A2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000747

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00214 AC: 299 AN: 139626 Hom.: 0 AF XY: 0.00221 AC XY: 165 AN XY: 74634

Gnomad AFR exome AF: 0.000299

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.000144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.000964

Gnomad NFE exome AF: 0.00431

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00415 AC: 4686 AN: 1128484 Hom.: 10 Cov.: 32 AF XY: 0.00407 AC XY: 2235 AN XY: 549200

Gnomad4 AFR exome AF: 0.000499

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000137

Gnomad4 EAS exome AF: 0.0000807

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00485

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74508

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00439

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00230 Hom.: 0

Bravo AF: 0.00234

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.74

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: rs41275468; hg19: chr1-11848143;