rs4629571

Positions:

• chr5-75362479-A-G
• chr5-75362479-A-T

Variant summary

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

The ENST00000680940.1(HMGCR):​c.*2137A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 152,246 control chromosomes in the GnomAD database, including 700 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 0.088 (700 hom., cov: 32)
• Consequence: HMGCR ENST00000680940.1 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.19

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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000680940.1	c.*2137A>G		3_prime_UTR_variant	21/21			ENSP00000505561	P1
HMGCR	ENST00000681271.1	c.*2137A>G		3_prime_UTR_variant	21/21			ENSP00000505805	P1
HMGCR	ENST00000681410.1	c.*2137A>G		3_prime_UTR_variant	20/20			ENSP00000506232	P1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13456 AN: 152128 Hom.: 695 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.107

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0885 AC: 13467 AN: 152246 Hom.: 700 Cov.: 32 AF XY: 0.0889 AC XY: 6618 AN XY: 74446

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.0787

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0697

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0750

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0958 Hom.: 86

Bravo AF: 0.0858

Asia WGS AF: 0.117 AC: 408 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	-0.84
CADD	Benign	6.2
DANN	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4629571; hg19: chr5-74658304;