Variant 5-75360350-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000859.3(HMGCR):c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,610,820 control chromosomes in the GnomAD database, including 7,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.082 ( 592 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7383 hom. )

Consequence

HMGCR
NM_000859.3 3_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.242

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 5-75360350-G-A is Benign according to our data. Variant chr5-75360350-G-A is described in ClinVar as [Benign]. Clinvar id is 3060727.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3 link	c.*8G>A		3_prime_UTR_variant	Exon 20 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.*8G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_000859.3	ENSP00000287936.4		P04035-1

Frequencies

GnomAD3 genomes

AF:

0.0818

AC:

12431

AN:

152052

Hom.:

591

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0326

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0975

Gnomad OTH

AF:

0.0708

GnomAD3 exomes

AF:

0.104

AC:

25777

AN:

248668

Hom.:

1576

AF XY:

0.105

AC XY:

14053

AN XY:

134360

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.156

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.0269

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.0977

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.0963

AC:

140447

AN:

1458650

Hom.:

7383

Cov.:

AF XY:

0.0975

AC XY:

70774

AN XY:

725698

show subpopulations

Gnomad4 AFR exome

AF:

0.0293

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.171

Gnomad4 EAS exome

AF:

0.0188

Gnomad4 SAS exome

AF:

0.124

Gnomad4 FIN exome

AF:

0.110

Gnomad4 NFE exome

AF:

0.0947

Gnomad4 OTH exome

AF:

0.0936

GnomAD4 genome

AF:

0.0817

AC:

12427

AN:

152170

Hom.:

592

Cov.:

AF XY:

0.0829

AC XY:

6167

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0325

Gnomad4 AMR

AF:

0.116

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.0271

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.0975

Gnomad4 OTH

AF:

0.0701

Alfa

AF:

0.0962

Hom.:

1854

Bravo

AF:

0.0765

Asia WGS

AF:

0.0750

AC:

260

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HMGCR-related disorder

Benign:1

Nov 25, 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

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.3

DANN

Benign

0.59

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