rs3761740

Positions:

• chr5-75336308-C-A

Variant summary

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

The variant allele was found at a frequency of 0.0914 in 260,978 control chromosomes in the GnomAD database, including 1,288 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 0.082 (595 hom., cov: 32)
  • Exomes 𝑓: 0.10 (693 hom.)
• Consequence: intergenic_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860

Genes affected

(HGNC:):

HMGCR (HGNC:5006): (3-hydroxy-3-methylglutaryl-CoA reductase) HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -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 = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.75336308C>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000247372	ENST00000501886.2	n.106+501G>T		intron_variant		4
HMGCR	ENST00000511206.5	c.-333C>A		upstream_gene_variant		2		ENSP00000426745.1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12433 AN: 151930 Hom.: 594 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0707

GnomAD4 exome AF: 0.105 AC: 11421 AN: 108930 Hom.: 693 Cov.: 0 AF XY: 0.108 AC XY: 6560 AN XY: 60992

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.0267

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.0982

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0817 AC: 12429 AN: 152048 Hom.: 595 Cov.: 32 AF XY: 0.0830 AC XY: 6171 AN XY: 74306

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0270

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0975

Gnomad4 OTH AF: 0.0700

Alfa AF: 0.0976 Hom.: 1099

Bravo AF: 0.0766

Asia WGS AF: 0.0760 AC: 263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.8
DANN	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3761740; hg19: chr5-74632133;