chr5-75338648-A-G

Variant names:

• chr5-75338648-A-G
• rs4704209
• NM_000859.3:c.-24+1348A>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.-24+1348A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 152,284 control chromosomes in the GnomAD database, including 307 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 0.056 (307 hom., cov: 31)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627
• Publications: 6 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 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.-24+1348A>G		intron	N/A	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.-24+1438A>G		intron	N/A	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.-24+1348A>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.-24+1348A>G		intron	N/A	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.-24+1348A>G		intron	N/A	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000511206.5	TSL:2	c.-24+2031A>G		intron	N/A	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8467 AN: 152166 Hom.: 306 Cov.: 31

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.0550

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

GnomAD4 genome AF: 0.0557 AC: 8475 AN: 152284 Hom.: 307 Cov.: 31 AF XY: 0.0579 AC XY: 4311 AN XY: 74468

African (AFR) AF: 0.0338 AC: 1406 AN: 41564

American (AMR) AF: 0.0756 AC: 1155 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.183 AC: 947 AN: 5184

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4828

European-Finnish (FIN) AF: 0.0853 AC: 904 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0544 AC: 3703 AN: 68032

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0500 Hom.: 161

Bravo AF: 0.0560

Asia WGS AF: 0.114 AC: 395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.69
PhyloP100		-0.63
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: rs4704209; hg19: chr5-74634473;