rs191835914

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000859.3(HMGCR):c.932A>C(p.Tyr311Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,613,224 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 10 hom. )

Consequence

HMGCR
NM_000859.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.31

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01021263).

BP6

Variant 5-75350940-A-C is Benign according to our data. Variant chr5-75350940-A-C is described in ClinVar as [Benign]. Clinvar id is 3053372.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000827 (126/152312) while in subpopulation EAS AF= 0.0158 (82/5184). AF 95% confidence interval is 0.0131. There are 3 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3 link	c.932A>C	p.Tyr311Ser	missense_variant	Exon 9 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.932A>C	p.Tyr311Ser	missense_variant	Exon 9 of 20	1	NM_000859.3	ENSP00000287936.4		P04035-1

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00156

AC:

389

AN:

250052

Hom.:

AF XY:

0.00148

AC XY:

200

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.0151

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000685

AC:

1001

AN:

1460912

Hom.:

Cov.:

AF XY:

0.000654

AC XY:

475

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.0156

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.00200

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000827

AC:

126

AN:

152312

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000916

Hom.:

Bravo

AF:

0.000763

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00178

AC:

216

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HMGCR-related disorder

Benign:1

Aug 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.71

D;D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.057

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.18

B;B;P

Vest4

0.74

MVP

0.50

MPC

1.5

ClinPred

0.089

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over