rs17244841

Variant names:

• chr5-75347030-A-T
• rs17244841
• NM_000859.3:c.451-174A>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.451-174A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 152,270 control chromosomes in the GnomAD database, including 210 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 0.041 (210 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.50
• Publications: 46 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]

HMGCR Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal recessive 28

  Inheritance: AR Classification: STRONG, MODERATE 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.451-174A>T		intron_variant	Intron 5 of 19	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.451-174A>T		intron_variant	Intron 5 of 19	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6197 AN: 152152 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0850

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0426

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

GnomAD4 genome AF: 0.0408 AC: 6209 AN: 152270 Hom.: 210 Cov.: 32 AF XY: 0.0387 AC XY: 2881 AN XY: 74466

African (AFR) AF: 0.0851 AC: 3535 AN: 41552

American (AMR) AF: 0.0256 AC: 391 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 164 AN: 3472

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5182

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1818 AN: 68008

Other (OTH) AF: 0.0417 AC: 88 AN: 2110

Alfa AF: 0.0359 Hom.: 17

Bravo AF: 0.0444

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.040
DANN	Benign	0.20
PhyloP100		-4.5
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: rs17244841; hg19: chr5-74642855;