5-75360714-T-C

Variant names:

• chr5-75360714-T-C
• rs12916
• NM_000859.3:c.*372T>C

Variant summary

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

The NM_000859.3(HMGCR):​c.*372T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 176,380 control chromosomes in the GnomAD database, including 13,341 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 0.37 (11234 hom., cov: 32)
  • Exomes 𝑓: 0.41 (2107 hom.)
• Consequence: HMGCR NM_000859.3 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.166
• Publications: 222 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.*372T>C		3_prime_UTR	Exon 20 of 20	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.*372T>C		3_prime_UTR	Exon 20 of 20	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.*372T>C		3_prime_UTR	Exon 19 of 19	NP_001124468.1	P04035-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.*372T>C		3_prime_UTR	Exon 20 of 20	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.*372T>C		3_prime_UTR	Exon 19 of 19	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000511206.5	TSL:2	c.*372T>C		3_prime_UTR	Exon 20 of 20	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56748 AN: 151946 Hom.: 11228 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.413 AC: 10038 AN: 24316 Hom.: 2107 Cov.: 0 AF XY: 0.419 AC XY: 5229 AN XY: 12488

African (AFR) AF: 0.249 AC: 208 AN: 834

American (AMR) AF: 0.396 AC: 778 AN: 1964

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 387 AN: 826

East Asian (EAS) AF: 0.542 AC: 887 AN: 1638

South Asian (SAS) AF: 0.536 AC: 550 AN: 1026

European-Finnish (FIN) AF: 0.449 AC: 595 AN: 1326

Middle Eastern (MID) AF: 0.477 AC: 41 AN: 86

European-Non Finnish (NFE) AF: 0.398 AC: 6013 AN: 15122

Other (OTH) AF: 0.388 AC: 579 AN: 1494

GnomAD4 genome AF: 0.373 AC: 56781 AN: 152064 Hom.: 11234 Cov.: 32 AF XY: 0.380 AC XY: 28244 AN XY: 74330

African (AFR) AF: 0.247 AC: 10234 AN: 41508

American (AMR) AF: 0.394 AC: 6018 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1624 AN: 3468

East Asian (EAS) AF: 0.533 AC: 2758 AN: 5174

South Asian (SAS) AF: 0.550 AC: 2653 AN: 4822

European-Finnish (FIN) AF: 0.452 AC: 4767 AN: 10550

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27503 AN: 67956

Other (OTH) AF: 0.367 AC: 776 AN: 2114

Alfa AF: 0.398 Hom.: 52110

Bravo AF: 0.359

Asia WGS AF: 0.523 AC: 1814 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	-0.91
CADD	Benign	1.8
DANN	Benign	0.61
PhyloP100		-0.17
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: rs12916; hg19: chr5-74656539;