5-75341886-A-T

Position:

• chr5-75341886-A-T

Variant summary

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

The NM_000859.3(HMGCR):​c.-23-697A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 152,026 control chromosomes in the GnomAD database, including 11,387 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 0.38 (11387 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110

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]

HMGCR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.-23-697A>T		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.-23-697A>T		intron_variant		1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58062 AN: 151908 Hom.: 11381 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.382 AC: 58103 AN: 152026 Hom.: 11387 Cov.: 32 AF XY: 0.390 AC XY: 28992 AN XY: 74316

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.532

Gnomad4 SAS AF: 0.581

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.368

Alfa AF: 0.385 Hom.: 1430

Bravo AF: 0.370

Asia WGS AF: 0.546 AC: 1894 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.90

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: rs10038095; hg19: chr5-74637711;