5-75348881-T-G

Variant names:

• chr5-75348881-T-G
• rs6453131
• NM_000859.3:c.557-1161T>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.557-1161T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 151,984 control chromosomes in the GnomAD database, including 11,696 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 0.39 (11696 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349
• Publications: 7 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)
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.557-1161T>G		intron	N/A	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.557-1161T>G		intron	N/A	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.557-1161T>G		intron	N/A	NP_001124468.1	P04035-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.557-1161T>G		intron	N/A	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.557-1161T>G		intron	N/A	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000511206.5	TSL:2	c.557-1161T>G		intron	N/A	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58976 AN: 151868 Hom.: 11681 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.388 AC: 59033 AN: 151984 Hom.: 11696 Cov.: 32 AF XY: 0.395 AC XY: 29329 AN XY: 74300

African (AFR) AF: 0.355 AC: 14729 AN: 41456

American (AMR) AF: 0.388 AC: 5932 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1547 AN: 3466

East Asian (EAS) AF: 0.506 AC: 2611 AN: 5156

South Asian (SAS) AF: 0.544 AC: 2620 AN: 4818

European-Finnish (FIN) AF: 0.440 AC: 4656 AN: 10574

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.379 AC: 25718 AN: 67920

Other (OTH) AF: 0.370 AC: 781 AN: 2112

Alfa AF: 0.347 Hom.: 3376

Bravo AF: 0.378

Asia WGS AF: 0.519 AC: 1801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs6453131; hg19: chr5-74644706; COSMIC: COSV55316059; COSMIC: COSV55316059;