Variant rs3846662 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000859.3(HMGCR):c.1722+45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,607,750 control chromosomes in the GnomAD database, including 183,987 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 0.57 ( 27554 hom., cov: 33)

Exomes 𝑓: 0.46 ( 156433 hom. )

Consequence

HMGCR
NM_000859.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.624

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3 linkuse as main transcript	c.1722+45A>G		intron_variant		ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9 linkuse as main transcript	c.1722+45A>G		intron_variant		1	NM_000859.3	ENSP00000287936	P1	P04035-1

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86700

AN:

152034

Hom.:

27499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.872

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.515

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.588

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.531

GnomAD3 exomes

AF:

0.501

AC:

124743

AN:

249012

Hom.:

33054

AF XY:

0.498

AC XY:

67004

AN XY:

134538

show subpopulations

Gnomad AFR exome

AF:

0.883

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.534

Gnomad SAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.470

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.456

AC:

663948

AN:

1455598

Hom.:

156433

Cov.:

AF XY:

0.459

AC XY:

332322

AN XY:

723424

show subpopulations

Gnomad4 AFR exome

AF:

0.888

Gnomad4 AMR exome

AF:

0.462

Gnomad4 ASJ exome

AF:

0.525

Gnomad4 EAS exome

AF:

0.527

Gnomad4 SAS exome

AF:

0.583

Gnomad4 FIN exome

AF:

0.467

Gnomad4 NFE exome

AF:

0.427

Gnomad4 OTH exome

AF:

0.477

GnomAD4 genome

AF:

0.571

AC:

86812

AN:

152152

Hom.:

27554

Cov.:

AF XY:

0.571

AC XY:

42426

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.872

Gnomad4 AMR

AF:

0.482

Gnomad4 ASJ

AF:

0.515

Gnomad4 EAS

AF:

0.531

Gnomad4 SAS

AF:

0.587

Gnomad4 FIN

AF:

0.464

Gnomad4 NFE

AF:

0.432

Gnomad4 OTH

AF:

0.527

Alfa

AF:

0.457

Hom.:

39272

Bravo

AF:

0.581

Asia WGS

AF:

0.588

AC:

2044

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.8

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over