rs2303152

Variant names:

• chr5-75345882-G-A
• rs2303152
• NM_000859.3:c.450+224G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000859.3(HMGCR):​c.450+224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 152,100 control chromosomes in the GnomAD database, including 694 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 0.088 (694 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 26 publications found

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]

HMGCR Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal recessive 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.450+224G>A		intron_variant	Intron 5 of 19	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.450+224G>A		intron_variant	Intron 5 of 19	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13360 AN: 151982 Hom.: 689 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0704

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0879 AC: 13371 AN: 152100 Hom.: 694 Cov.: 32 AF XY: 0.0883 AC XY: 6569 AN XY: 74366

African (AFR) AF: 0.0581 AC: 2410 AN: 41464

American (AMR) AF: 0.0780 AC: 1193 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3468

East Asian (EAS) AF: 0.0702 AC: 364 AN: 5186

South Asian (SAS) AF: 0.168 AC: 806 AN: 4810

European-Finnish (FIN) AF: 0.0752 AC: 796 AN: 10580

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6949 AN: 67978

Other (OTH) AF: 0.102 AC: 216 AN: 2116

Alfa AF: 0.103 Hom.: 739

Bravo AF: 0.0851

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.48
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2303152; hg19: chr5-74641707; COSMIC: COSV55317957; COSMIC: COSV55317957;