rs3846663

Variant names:

• chr5-75359901-C-T
• rs3846663
• NM_000859.3:c.2458-84C>T

Variant summary

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

The NM_000859.3(HMGCR):​c.2458-84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,501,128 control chromosomes in the GnomAD database, including 116,821 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 0.36 (10290 hom., cov: 32)
  • Exomes 𝑓: 0.39 (106531 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281

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]

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.2458-84C>T		intron_variant	Intron 18 of 19	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.2458-84C>T		intron_variant	Intron 18 of 19	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54227 AN: 151952 Hom.: 10284 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.393 AC: 529904 AN: 1349058 Hom.: 106531 Cov.: 20 AF XY: 0.398 AC XY: 268956 AN XY: 675234

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.394

Gnomad4 ASJ exome AF: 0.456

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.388

GnomAD4 genome AF: 0.357 AC: 54262 AN: 152070 Hom.: 10290 Cov.: 32 AF XY: 0.364 AC XY: 27093 AN XY: 74348

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.532

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.348

Alfa AF: 0.382 Hom.: 15311

Bravo AF: 0.342

Asia WGS AF: 0.520 AC: 1805 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.4
DANN	Benign	0.32

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: rs3846663; hg19: chr5-74655726; COSMIC: COSV55314943; COSMIC: COSV55314943;