5-75360714-T-C

Position:

• chr5-75360714-T-C

Variant summary

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

The NM_000859.3(HMGCR):​c.*372T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 176,380 control chromosomes in the GnomAD database, including 13,341 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 0.37 (11234 hom., cov: 32)
  • Exomes 𝑓: 0.41 (2107 hom.)
• Consequence: HMGCR NM_000859.3 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.166

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]

HMGCR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.*372T>C		3_prime_UTR_variant	20/20	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.*372T>C		3_prime_UTR_variant	20/20	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56748 AN: 151946 Hom.: 11228 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.413 AC: 10038 AN: 24316 Hom.: 2107 Cov.: 0 AF XY: 0.419 AC XY: 5229 AN XY: 12488

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.469

Gnomad4 EAS exome AF: 0.542

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.388

GnomAD4 genome AF: 0.373 AC: 56781 AN: 152064 Hom.: 11234 Cov.: 32 AF XY: 0.380 AC XY: 28244 AN XY: 74330

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.367

Alfa AF: 0.402 Hom.: 23154

Bravo AF: 0.359

Asia WGS AF: 0.523 AC: 1814 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

- poor metabolizer

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.61

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: rs12916; hg19: chr5-74656539;