rs5908

Positions:

• chr5-75356374-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 BS2

The NM_000859.3(HMGCR):​c.1912A>G​(p.Ile638Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,600,270 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (12 hom., cov: 33)
  • Exomes 𝑓: 0.018 (328 hom.)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514

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]

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HMGCR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HMGCR. . Gene score misZ 3.7591 (greater than the threshold 3.09). Trascript score misZ 4.2252 (greater than threshold 3.09). GenCC has associacion of gene with muscular dystrophy, limb-girdle, autosomal recessive 28.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006518215).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2006/152374) while in subpopulation NFE AF= 0.0211 (1435/68036). AF 95% confidence interval is 0.0202. There are 12 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.1912A>G	p.Ile638Val	missense_variant	15/20	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.1912A>G	p.Ile638Val	missense_variant	15/20	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2007 AN: 152256 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0135 AC: 3255 AN: 241732 Hom.: 36 AF XY: 0.0139 AC XY: 1820 AN XY: 130808

Gnomad AFR exome AF: 0.00299

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0184 AC: 26698 AN: 1447896 Hom.: 328 Cov.: 27 AF XY: 0.0180 AC XY: 12970 AN XY: 720438

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.00514

Gnomad4 ASJ exome AF: 0.00516

Gnomad4 EAS exome AF: 0.0000768

Gnomad4 SAS exome AF: 0.00863

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0132 AC: 2006 AN: 152374 Hom.: 12 Cov.: 33 AF XY: 0.0130 AC XY: 965 AN XY: 74508

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0186 Hom.: 45

Bravo AF: 0.0112

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0190 AC: 163

ExAC AF: 0.0137 AC: 1666

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.8
DANN	Benign	0.77
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.79	.;T;T
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.013
MPC		0.69
ClinPred		0.0059	T
GERP RS		-2.0
Varity_R		0.058
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs5908; hg19: chr5-74652199; COSMIC: COSV99072895; COSMIC: COSV99072895;