rs3846663

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 97 publications found

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]

CERT1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 34

  Inheritance: AD Classification: DEFINITIVE, STRONG 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=-0.9).
• 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

African (AFR) AF: 0.239 AC: 7511 AN: 31368

American (AMR) AF: 0.394 AC: 17271 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11155 AN: 24438

East Asian (EAS) AF: 0.527 AC: 20566 AN: 39042

South Asian (SAS) AF: 0.542 AC: 44425 AN: 81962

European-Finnish (FIN) AF: 0.439 AC: 23085 AN: 52572

Middle Eastern (MID) AF: 0.406 AC: 2233 AN: 5502

European-Non Finnish (NFE) AF: 0.377 AC: 381680 AN: 1013722

Other (OTH) AF: 0.388 AC: 21978 AN: 56634

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

African (AFR) AF: 0.240 AC: 9951 AN: 41470

American (AMR) AF: 0.377 AC: 5765 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3470

East Asian (EAS) AF: 0.532 AC: 2743 AN: 5154

South Asian (SAS) AF: 0.546 AC: 2638 AN: 4828

European-Finnish (FIN) AF: 0.441 AC: 4672 AN: 10590

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25768 AN: 67974

Other (OTH) AF: 0.348 AC: 734 AN: 2108

Alfa AF: 0.379 Hom.: 39100

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
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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