rs2241402

chr5-75350430-T-Achr5-75350430-T-G

Variant summary

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

The NM_000859.3(HMGCR):c.780+56T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0568 in 1,190,780 control chromosomes in the GnomAD database, including 2,458 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 0.055 (304 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2154 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.780+56T>A		intron_variant		ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.780+56T>A		intron_variant		1	NM_000859.3	P1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8393 AN: 152104 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.0551

GnomAD4 exome AF: 0.0570 AC: 59199 AN: 1038558 Hom.: 2154 AF XY: 0.0556 AC XY: 29541 AN XY: 531506

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.0875

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0850

Gnomad4 NFE exome AF: 0.0534

Gnomad4 OTH exome AF: 0.0559

GnomAD4 genome AF: 0.0552 AC: 8401 AN: 152222 Hom.: 304 Cov.: 32 AF XY: 0.0575 AC XY: 4276 AN XY: 74428

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.0754

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.0544

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0547 Hom.: 34

Bravo AF: 0.0555

Asia WGS AF: 0.116 AC: 402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.4
Dann	Benign	0.37

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: rs2241402; hg19: chr5-74646255; COSMIC: COSV55317402; COSMIC: COSV55317402;