5-75355259-A-G

Variant names:

• chr5-75355259-A-G
• rs3846662
• NM_000859.3:c.1722+45A>G

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.624
• Publications: 186 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.1722+45A>G		intron	N/A	NP_000850.1
	HMGCR	NM_001364187.1		c.1722+45A>G		intron	N/A	NP_001351116.1
	HMGCR	NM_001130996.2		c.1564-106A>G		intron	N/A	NP_001124468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.1722+45A>G		intron	N/A	ENSP00000287936.4
	HMGCR	ENST00000343975.9	TSL:1	c.1564-106A>G		intron	N/A	ENSP00000340816.5
	HMGCR	ENST00000508070.1	TSL:3	n.80A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86700 AN: 152034 Hom.: 27499 Cov.: 33

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

GnomAD2 exomes AF: 0.501 AC: 124743 AN: 249012 AF XY: 0.498

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 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.: 32 AF XY: 0.459 AC XY: 332322 AN XY: 723424

African (AFR) AF: 0.888 AC: 29565 AN: 33296

American (AMR) AF: 0.462 AC: 20509 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13657 AN: 25990

East Asian (EAS) AF: 0.527 AC: 20875 AN: 39580

South Asian (SAS) AF: 0.583 AC: 50075 AN: 85958

European-Finnish (FIN) AF: 0.467 AC: 24903 AN: 53318

Middle Eastern (MID) AF: 0.522 AC: 2996 AN: 5734

European-Non Finnish (NFE) AF: 0.427 AC: 472711 AN: 1107212

Other (OTH) AF: 0.477 AC: 28657 AN: 60100

GnomAD4 genome AF: 0.571 AC: 86812 AN: 152152 Hom.: 27554 Cov.: 33 AF XY: 0.571 AC XY: 42426 AN XY: 74350

African (AFR) AF: 0.872 AC: 36236 AN: 41538

American (AMR) AF: 0.482 AC: 7370 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1789 AN: 3472

East Asian (EAS) AF: 0.531 AC: 2750 AN: 5176

South Asian (SAS) AF: 0.587 AC: 2832 AN: 4824

European-Finnish (FIN) AF: 0.464 AC: 4898 AN: 10550

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29335 AN: 67978

Other (OTH) AF: 0.527 AC: 1113 AN: 2112

Alfa AF: 0.476 Hom.: 88860

Bravo AF: 0.581

Asia WGS AF: 0.588 AC: 2044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.8
DANN	Benign	0.47
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3846662; hg19: chr5-74651084; COSMIC: COSV55314644; COSMIC: COSV55314644;