rs12654264

Positions:

• chr5-75352778-A-T

Variant summary

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

The ENST00000287936.9(HMGCR):​c.1368+1176A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,936 control chromosomes in the GnomAD database, including 11,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.38 (11365 hom., cov: 31)
• Consequence: HMGCR ENST00000287936.9 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.106

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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.1368+1176A>T		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.1368+1176A>T		intron_variant		1	NM_000859.3	ENSP00000287936	P1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58007 AN: 151818 Hom.: 11359 Cov.: 31

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.382 AC: 58048 AN: 151936 Hom.: 11365 Cov.: 31 AF XY: 0.390 AC XY: 28925 AN XY: 74242

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.532

Gnomad4 SAS AF: 0.580

Gnomad4 FIN AF: 0.440

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.368

Alfa AF: 0.387 Hom.: 6347

Bravo AF: 0.370

Asia WGS AF: 0.548 AC: 1902 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Low density lipoprotein cholesterol level quantitative trait locus 3 Other:1

association, no assertion criteria provided

literature only

OMIM

Mar 20, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12654264; hg19: chr5-74648603;