5-75348881-T-G

Position:

• chr5-75348881-T-G

Variant summary

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

The ENST00000287936.9(HMGCR):​c.557-1161T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 151,984 control chromosomes in the GnomAD database, including 11,696 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 0.39 (11696 hom., cov: 32)
• Consequence: HMGCR ENST00000287936.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.557-1161T>G		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.557-1161T>G		intron_variant		1	NM_000859.3	ENSP00000287936	P1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58976 AN: 151868 Hom.: 11681 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.388 AC: 59033 AN: 151984 Hom.: 11696 Cov.: 32 AF XY: 0.395 AC XY: 29329 AN XY: 74300

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.440

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.370

Alfa AF: 0.271 Hom.: 725

Bravo AF: 0.378

Asia WGS AF: 0.519 AC: 1801 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	6.7
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs6453131; hg19: chr5-74644706; COSMIC: COSV55316059; COSMIC: COSV55316059;