5-75356374-A-G

Variant names:

• chr5-75356374-A-G
• rs5908
• NM_000859.3:c.1912A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 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]

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]

CERT1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 34

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.7591 (above the threshold of 3.09). Trascript score misZ: 4.2252 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.1912A>G	p.Ile638Val	missense	Exon 15 of 20	NP_000850.1
	HMGCR	NM_001364187.1		c.1912A>G	p.Ile638Val	missense	Exon 15 of 20	NP_001351116.1
	HMGCR	NM_001130996.2		c.1753A>G	p.Ile585Val	missense	Exon 14 of 19	NP_001124468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.1912A>G	p.Ile638Val	missense	Exon 15 of 20	ENSP00000287936.4
	HMGCR	ENST00000343975.9	TSL:1	c.1753A>G	p.Ile585Val	missense	Exon 14 of 19	ENSP00000340816.5
	HMGCR	ENST00000511206.5	TSL:2	c.1912A>G	p.Ile638Val	missense	Exon 15 of 20	ENSP00000426745.1

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

GnomAD2 exomes AF: 0.0135 AC: 3255 AN: 241732 AF XY: 0.0139

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 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

African (AFR) AF: 0.00249 AC: 81 AN: 32564

American (AMR) AF: 0.00514 AC: 221 AN: 42996

Ashkenazi Jewish (ASJ) AF: 0.00516 AC: 133 AN: 25788

East Asian (EAS) AF: 0.0000768 AC: 3 AN: 39042

South Asian (SAS) AF: 0.00863 AC: 727 AN: 84222

European-Finnish (FIN) AF: 0.0196 AC: 1044 AN: 53218

Middle Eastern (MID) AF: 0.00297 AC: 17 AN: 5718

European-Non Finnish (NFE) AF: 0.0213 AC: 23563 AN: 1104526

Other (OTH) AF: 0.0152 AC: 909 AN: 59822

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

African (AFR) AF: 0.00344 AC: 143 AN: 41598

American (AMR) AF: 0.00653 AC: 100 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.0229 AC: 243 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1435 AN: 68036

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0179 Hom.: 109

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 v4.9

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
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		-0.51
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.13
Sift	Benign	0.58	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.69
ClinPred		0.0059	T
GERP RS		-2.0
Varity_R		0.058
gMVP		0.68
Mutation Taster		=100/0	polymorphism

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