rs17238540

Positions:

• chr5-75359673-T-G

Variant summary

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

The NM_000859.3(HMGCR):​c.2457+117T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 909,748 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.038 (198 hom., cov: 32)
  • Exomes 𝑓: 0.023 (282 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185

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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.2457+117T>G		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.2457+117T>G		intron_variant		1	NM_000859.3	ENSP00000287936	P1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5831 AN: 152202 Hom.: 198 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0231 AC: 17534 AN: 757428 Hom.: 282 Cov.: 10 AF XY: 0.0222 AC XY: 8613 AN XY: 387356

Gnomad4 AFR exome AF: 0.0863

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0397

Gnomad4 EAS exome AF: 0.0000599

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome AF: 0.0383 AC: 5840 AN: 152320 Hom.: 198 Cov.: 32 AF XY: 0.0361 AC XY: 2688 AN XY: 74480

Gnomad4 AFR AF: 0.0832

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0355

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.0245

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0275 Hom.: 67

Bravo AF: 0.0418

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.40

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: rs17238540; hg19: chr5-74655498;