rs10515198

Variant names:

• chr5-75345735-G-A
• rs10515198
• NM_000859.3:c.450+77G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-75345735-G-A
• chr5-75345735-G-C

Variant summary

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

The NM_000859.3(HMGCR):​c.450+77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 874,494 control chromosomes in the GnomAD database, including 4,554 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 0.082 (592 hom., cov: 32)
  • Exomes 𝑓: 0.098 (3962 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.771
• Publications: 16 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 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.450+77G>A		intron	N/A	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.450+77G>A		intron	N/A	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.450+77G>A		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.450+77G>A		intron	N/A	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.450+77G>A		intron	N/A	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000511206.5	TSL:2	c.450+77G>A		intron	N/A	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12439 AN: 152032 Hom.: 591 Cov.: 32

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0705

GnomAD4 exome AF: 0.0981 AC: 70876 AN: 722344 Hom.: 3962 AF XY: 0.0998 AC XY: 38436 AN XY: 384964

African (AFR) AF: 0.0315 AC: 566 AN: 17946

American (AMR) AF: 0.141 AC: 5084 AN: 36022

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3404 AN: 20122

East Asian (EAS) AF: 0.0184 AC: 652 AN: 35518

South Asian (SAS) AF: 0.124 AC: 8177 AN: 65830

European-Finnish (FIN) AF: 0.110 AC: 5371 AN: 48990

Middle Eastern (MID) AF: 0.0722 AC: 299 AN: 4144

European-Non Finnish (NFE) AF: 0.0959 AC: 43935 AN: 458222

Other (OTH) AF: 0.0953 AC: 3388 AN: 35550

GnomAD4 genome AF: 0.0817 AC: 12435 AN: 152150 Hom.: 592 Cov.: 32 AF XY: 0.0830 AC XY: 6173 AN XY: 74390

African (AFR) AF: 0.0326 AC: 1355 AN: 41516

American (AMR) AF: 0.116 AC: 1768 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3472

East Asian (EAS) AF: 0.0266 AC: 138 AN: 5182

South Asian (SAS) AF: 0.121 AC: 582 AN: 4822

European-Finnish (FIN) AF: 0.111 AC: 1172 AN: 10572

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0976 AC: 6635 AN: 67984

Other (OTH) AF: 0.0698 AC: 147 AN: 2106

Alfa AF: 0.0939 Hom.: 964

Bravo AF: 0.0766

Asia WGS AF: 0.0760 AC: 263 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.0
DANN	Benign	0.71
PhyloP100		-0.77
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: rs10515198; hg19: chr5-74641560;