rs5908

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.514

Publications

35 publications found

Variant links:

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 links:

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)

CERT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3 link	c.1912A>G	p.Ile638Val	missense_variant	Exon 15 of 20	ENST00000287936.9	NP_000850.1	P04035-1A0A024RAP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9 link	c.1912A>G	p.Ile638Val	missense_variant	Exon 15 of 20	1	NM_000859.3	ENSP00000287936.4		P04035-1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2007

AN:

152256

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0180

AC XY:

12970

AN XY:

720438

show subpopulations

African (AFR)

AF:

0.00249

AC:

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:

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:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0213

AC:

23563

AN:

1104526

Other (OTH)

AF:

0.0152

AC:

909

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1035

2070

3104

4139

5174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0132

AC:

2006

AN:

152374

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

965

AN XY:

74508

show subpopulations

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:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00724

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0229

AC:

243

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1435

AN:

68036

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0179

Hom.:

109

Bravo

AF:

0.0112

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0190

AC:

163

ExAC

AF:

0.0137

AC:

1666

Asia WGS

AF:

0.00289

AC:

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

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.8

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.20

T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.79

.;T;T

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

N;N;.

PhyloP100

-0.51

PrimateAI

Benign

0.31

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

GERP RS

-2.0

Varity_R

0.058

gMVP

0.68

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over