rs10515198

chr5-75345735-G-A

Variant summary

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

The NM_000859.3(HMGCR):c.450+77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 874,494 control chromosomes in the GnomAD database, including 4,554 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 (592 hom., cov: 32)
  • Exomes 𝑓: 0.098 (3962 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.771

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=-0.87).
• 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	UniProt
HMGCR	NM_000859.3	c.450+77G>A		intron_variant		ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.450+77G>A		intron_variant		1	NM_000859.3	P1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12439 AN: 152032 Hom.: 591 Cov.: 32

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0705

GnomAD4 exome AF: 0.0981 AC: 70876 AN: 722344 Hom.: 3962 AF XY: 0.0998 AC XY: 38436 AN XY: 384964

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0959

Gnomad4 OTH exome AF: 0.0953

GnomAD4 genome AF: 0.0817 AC: 12435 AN: 152150 Hom.: 592 Cov.: 32 AF XY: 0.0830 AC XY: 6173 AN XY: 74390

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0266

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0976

Gnomad4 OTH AF: 0.0698

Alfa AF: 0.0966 Hom.: 766

Bravo AF: 0.0766

Asia WGS AF: 0.0760 AC: 263 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.0
Dann	Benign	0.71

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: rs10515198; hg19: chr5-74641560;