rs12654264

Variant names:

• chr5-75352778-A-T
• rs12654264
• NM_000859.3:c.1368+1176A>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.1368+1176A>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 151,936 control chromosomes in the GnomAD database, including 11,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.38 (11365 hom., cov: 31)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.106
• Publications: 109 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.562 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.1368+1176A>T		intron	N/A	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.1368+1176A>T		intron	N/A	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.1368+1176A>T		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.1368+1176A>T		intron	N/A	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.1368+1176A>T		intron	N/A	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000511206.5	TSL:2	c.1368+1176A>T		intron	N/A	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58007 AN: 151818 Hom.: 11359 Cov.: 31

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.440

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: 58048 AN: 151936 Hom.: 11365 Cov.: 31 AF XY: 0.390 AC XY: 28925 AN XY: 74242

African (AFR) AF: 0.324 AC: 13434 AN: 41418

American (AMR) AF: 0.384 AC: 5863 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1597 AN: 3466

East Asian (EAS) AF: 0.532 AC: 2738 AN: 5150

South Asian (SAS) AF: 0.580 AC: 2799 AN: 4826

European-Finnish (FIN) AF: 0.440 AC: 4637 AN: 10544

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25764 AN: 67942

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.387 Hom.: 6347

Bravo AF: 0.370

Asia WGS AF: 0.548 AC: 1902 AN: 3478

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Low density lipoprotein cholesterol level quantitative trait locus 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.0
DANN	Benign	0.73
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12654264;

hg19: chr5-74648603;