rs3761740

Variant names:

• chr5-75336308-C-A
• rs3761740
• ENST00000501886.2:n.106+501G>T

Variant summary

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

The ENST00000501886.2(ENSG00000247372):​n.106+501G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 260,978 control chromosomes in the GnomAD database, including 1,288 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 0.082 (595 hom., cov: 32)
  • Exomes 𝑓: 0.10 (693 hom.)
• Consequence: ENSG00000247372 ENST00000501886.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• Publications: 36 publications found

Genes affected

ENSG00000247372 (HGNC:):

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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	XM_011543357.2	c.-273C>A		upstream_gene_variant			XP_011541659.1
HMGCR	XM_011543359.2	c.-273C>A		upstream_gene_variant			XP_011541661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000247372	ENST00000501886.2	n.106+501G>T		intron_variant	Intron 1 of 2	4
HMGCR	ENST00000511206.5	c.-333C>A		upstream_gene_variant		2		ENSP00000426745.1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12433 AN: 151930 Hom.: 594 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0707

GnomAD4 exome AF: 0.105 AC: 11421 AN: 108930 Hom.: 693 Cov.: 0 AF XY: 0.108 AC XY: 6560 AN XY: 60992

African (AFR) AF: 0.0277 AC: 70 AN: 2530

American (AMR) AF: 0.139 AC: 729 AN: 5260

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 412 AN: 2426

East Asian (EAS) AF: 0.0267 AC: 99 AN: 3704

South Asian (SAS) AF: 0.126 AC: 3141 AN: 24986

European-Finnish (FIN) AF: 0.117 AC: 495 AN: 4224

Middle Eastern (MID) AF: 0.0642 AC: 24 AN: 374

European-Non Finnish (NFE) AF: 0.0982 AC: 5927 AN: 60350

Other (OTH) AF: 0.103 AC: 524 AN: 5076

GnomAD4 genome AF: 0.0817 AC: 12429 AN: 152048 Hom.: 595 Cov.: 32 AF XY: 0.0830 AC XY: 6171 AN XY: 74306

African (AFR) AF: 0.0325 AC: 1346 AN: 41458

American (AMR) AF: 0.116 AC: 1772 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3470

East Asian (EAS) AF: 0.0270 AC: 140 AN: 5184

South Asian (SAS) AF: 0.121 AC: 580 AN: 4808

European-Finnish (FIN) AF: 0.111 AC: 1175 AN: 10554

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0975 AC: 6630 AN: 67986

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0946 Hom.: 2248

Bravo AF: 0.0766

Asia WGS AF: 0.0760 AC: 263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.8
DANN	Benign	0.75
PhyloP100		0.086
PromoterAI		-0.13	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3761740; hg19: chr5-74632133;