Variant 19-11128131-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000527.5(LDLR):c.2389+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,553,346 control chromosomes in the GnomAD database, including 47,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4112 hom., cov: 31)

Exomes 𝑓: 0.25 ( 43561 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.00

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-11128131-C-T is Benign according to our data. Variant chr19-11128131-C-T is described in ClinVar as [Benign]. Clinvar id is 265907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11128131-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2389+46C>T		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2389+46C>T		intron_variant		1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34227

AN:

151926

Hom.:

4107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.226

GnomAD3 exomes

AF:

0.245

AC:

61232

AN:

250118

Hom.:

7918

AF XY:

0.241

AC XY:

32605

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.160

Gnomad AMR exome

AF:

0.256

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.383

Gnomad SAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.223

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.246

AC:

344863

AN:

1401302

Hom.:

43561

Cov.:

AF XY:

0.244

AC XY:

170809

AN XY:

700566

show subpopulations

Gnomad4 AFR exome

AF:

0.149

Gnomad4 AMR exome

AF:

0.256

Gnomad4 ASJ exome

AF:

0.215

Gnomad4 EAS exome

AF:

0.400

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.233

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.225

AC:

34251

AN:

152044

Hom.:

4112

Cov.:

AF XY:

0.224

AC XY:

16618

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.161

Gnomad4 AMR

AF:

0.238

Gnomad4 ASJ

AF:

0.209

Gnomad4 EAS

AF:

0.385

Gnomad4 SAS

AF:

0.192

Gnomad4 FIN

AF:

0.220

Gnomad4 NFE

AF:

0.254

Gnomad4 OTH

AF:

0.225

Alfa

AF:

0.178

Hom.:

529

Bravo

AF:

0.227

Asia WGS

AF:

0.295

AC:

1023

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.052

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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