5-75359626-C-T

Variant names:

• chr5-75359626-C-T
• rs2303151
• NM_000859.3:c.2457+70C>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.2457+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,311,974 control chromosomes in the GnomAD database, including 2,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.056 (304 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2440 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.673
• Publications: 15 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000859.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.2457+70C>T		intron	N/A	NP_000850.1
	HMGCR	NM_001364187.1		c.2457+70C>T		intron	N/A	NP_001351116.1
	HMGCR	NM_001130996.2		c.2298+70C>T		intron	N/A	NP_001124468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.2457+70C>T		intron	N/A	ENSP00000287936.4
	HMGCR	ENST00000343975.9	TSL:1	c.2298+70C>T		intron	N/A	ENSP00000340816.5
	HMGCR	ENST00000509085.5	TSL:1	c.285+316C>T		intron	N/A	ENSP00000421378.1

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8466 AN: 152124 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.0590 AC: 68431 AN: 1159732 Hom.: 2440 Cov.: 15 AF XY: 0.0574 AC XY: 33602 AN XY: 585080

African (AFR) AF: 0.0359 AC: 962 AN: 26796

American (AMR) AF: 0.0906 AC: 3139 AN: 34650

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 400 AN: 21282

East Asian (EAS) AF: 0.172 AC: 6528 AN: 37924

South Asian (SAS) AF: 0.0237 AC: 1729 AN: 72990

European-Finnish (FIN) AF: 0.0855 AC: 4358 AN: 50954

Middle Eastern (MID) AF: 0.0237 AC: 82 AN: 3462

European-Non Finnish (NFE) AF: 0.0561 AC: 48362 AN: 862016

Other (OTH) AF: 0.0578 AC: 2871 AN: 49658

GnomAD4 genome AF: 0.0557 AC: 8474 AN: 152242 Hom.: 304 Cov.: 32 AF XY: 0.0578 AC XY: 4306 AN XY: 74434

African (AFR) AF: 0.0339 AC: 1407 AN: 41552

American (AMR) AF: 0.0757 AC: 1158 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.183 AC: 949 AN: 5182

South Asian (SAS) AF: 0.0314 AC: 151 AN: 4816

European-Finnish (FIN) AF: 0.0852 AC: 903 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0544 AC: 3698 AN: 68010

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0529 Hom.: 251

Bravo AF: 0.0559

Asia WGS AF: 0.114 AC: 395 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Statins, attenuated cholesterol lowering by Other:1

Nov 01, 2022

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

likely responsive

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.27
PhyloP100		-0.67
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: rs2303151; hg19: chr5-74655451;