rs4629571

Variant names:

• chr5-75362479-A-G
• rs4629571
• ENST00000680940.1:c.*2137A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-75362479-A-G
• chr5-75362479-A-T

Variant summary

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

The ENST00000680940.1(HMGCR):​c.*2137A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 152,246 control chromosomes in the GnomAD database, including 700 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 0.088 (700 hom., cov: 32)
• Consequence: HMGCR ENST00000680940.1 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.19
• Publications: 10 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000680940.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000680940.1		c.*2137A>G		3_prime_UTR	Exon 21 of 21	ENSP00000505561.1	P04035-1
	HMGCR	ENST00000681271.1		c.*2137A>G		3_prime_UTR	Exon 21 of 21	ENSP00000505805.1	P04035-1
	HMGCR	ENST00000681410.1		c.*2137A>G		3_prime_UTR	Exon 20 of 20	ENSP00000506232.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13456 AN: 152128 Hom.: 695 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.107

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0885 AC: 13467 AN: 152246 Hom.: 700 Cov.: 32 AF XY: 0.0889 AC XY: 6618 AN XY: 74446

African (AFR) AF: 0.0584 AC: 2427 AN: 41544

American (AMR) AF: 0.0787 AC: 1203 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 564 AN: 3470

East Asian (EAS) AF: 0.0697 AC: 361 AN: 5180

South Asian (SAS) AF: 0.170 AC: 822 AN: 4826

European-Finnish (FIN) AF: 0.0750 AC: 795 AN: 10604

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6994 AN: 68012

Other (OTH) AF: 0.105 AC: 221 AN: 2112

Alfa AF: 0.0945 Hom.: 89

Bravo AF: 0.0858

Asia WGS AF: 0.117 AC: 408 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Statins, attenuated cholesterol lowering by (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.83
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs4629571; hg19: chr5-74658304;