Variant 5-75356949-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS1

The NM_000859.3(HMGCR):c.1986+501G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 379,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

HMGCR
NM_000859.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.232

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.092580795).

BP6

Variant 5-75356949-G-A is Benign according to our data. Variant chr5-75356949-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2655534.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000157 (22/140150) while in subpopulation SAS AF= 0.000497 (2/4022). AF 95% confidence interval is 0.000139. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3 link	c.1986+501G>A		intron_variant	Intron 15 of 19	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.1986+501G>A		intron_variant	Intron 15 of 19	1	NM_000859.3	ENSP00000287936.4		P04035-1

Frequencies

GnomAD3 genomes

AF:

0.000157

AC:

AN:

140048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000781

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000354

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000174

Gnomad OTH

AF:

0.000527

GnomAD4 exome

AF:

0.000263

AC:

AN:

239564

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

AN XY:

121434

show subpopulations

Gnomad4 AFR exome

AF:

0.000284

Gnomad4 AMR exome

AF:

0.000411

Gnomad4 ASJ exome

AF:

0.000113

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000702

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000312

Gnomad4 OTH exome

AF:

0.000377

GnomAD4 genome

AF:

0.000157

AC:

AN:

140150

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

68184

show subpopulations

Gnomad4 AFR

AF:

0.0000779

Gnomad4 AMR

AF:

0.000354

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000497

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000174

Gnomad4 OTH

AF:

0.000521

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000147

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CERT1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Benign

0.40

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.27

MetaRNN

Benign

0.093

GERP RS

-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

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