5-75340659-C-A

Position:

• chr5-75340659-C-A

Variant summary

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

The NM_000859.3(HMGCR):​c.-23-1924C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,982 control chromosomes in the GnomAD database, including 10,109 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 0.35 (10109 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501

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]

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 = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.-23-1924C>A		intron_variant		ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.-23-1924C>A		intron_variant		1	NM_000859.3	P1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53750 AN: 151864 Hom.: 10103 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.354 AC: 53785 AN: 151982 Hom.: 10109 Cov.: 32 AF XY: 0.362 AC XY: 26862 AN XY: 74272

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.545

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.346

Alfa AF: 0.367 Hom.: 1339

Bravo AF: 0.339

Asia WGS AF: 0.508 AC: 1762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.53

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: rs10045497; hg19: chr5-74636484; COSMIC: COSV55314837; COSMIC: COSV55314837;