5-75355259-A-G

Position:

• chr5-75355259-A-G

Variant summary

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

The NM_000859.3(HMGCR):​c.1722+45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,607,750 control chromosomes in the GnomAD database, including 183,987 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 0.57 (27554 hom., cov: 33)
  • Exomes 𝑓: 0.46 (156433 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.624

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.1722+45A>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.1722+45A>G		intron_variant		1	NM_000859.3	ENSP00000287936	P1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86700 AN: 152034 Hom.: 27499 Cov.: 33

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.531

GnomAD3 exomes AF: 0.501 AC: 124743 AN: 249012 Hom.: 33054 AF XY: 0.498 AC XY: 67004 AN XY: 134538

Gnomad AFR exome AF: 0.883

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.534

Gnomad SAS exome AF: 0.585

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.456 AC: 663948 AN: 1455598 Hom.: 156433 Cov.: 32 AF XY: 0.459 AC XY: 332322 AN XY: 723424

Gnomad4 AFR exome AF: 0.888

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.571 AC: 86812 AN: 152152 Hom.: 27554 Cov.: 33 AF XY: 0.571 AC XY: 42426 AN XY: 74350

Gnomad4 AFR AF: 0.872

Gnomad4 AMR AF: 0.482

Gnomad4 ASJ AF: 0.515

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.464

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.527

Alfa AF: 0.457 Hom.: 39272

Bravo AF: 0.581

Asia WGS AF: 0.588 AC: 2044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.8
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3846662; hg19: chr5-74651084; COSMIC: COSV55314644; COSMIC: COSV55314644;