rs2303151

Positions:

• chr5-75359626-C-T

Variant summary

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

The NM_000859.3(HMGCR):​c.2457+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,311,974 control chromosomes in the GnomAD database, including 2,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.056 (304 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2440 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.673

Genes affected

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]

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.2457+70C>T		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.2457+70C>T		intron_variant		1	NM_000859.3	ENSP00000287936	P1

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8466 AN: 152124 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.0590 AC: 68431 AN: 1159732 Hom.: 2440 Cov.: 15 AF XY: 0.0574 AC XY: 33602 AN XY: 585080

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.0906

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0855

Gnomad4 NFE exome AF: 0.0561

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0557 AC: 8474 AN: 152242 Hom.: 304 Cov.: 32 AF XY: 0.0578 AC XY: 4306 AN XY: 74434

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.0757

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.0314

Gnomad4 FIN AF: 0.0852

Gnomad4 NFE AF: 0.0544

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0532 Hom.: 201

Bravo AF: 0.0559

Asia WGS AF: 0.114 AC: 395 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Statins, attenuated cholesterol lowering by Other:1

drug response, no assertion criteria provided

research

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Nov 01, 2022

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.27

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: rs2303151; hg19: chr5-74655451;