19-11110648-G-A

Position:

chr19-11110648-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1).BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics.BP4 - No REVEL, splicing evaluation needed.Functional data on splicing not available.A) variant located at -20 to +3 bases from canonical acceptor splice siteMES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64.Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0B) variant is intronicC) variant is intronicVariant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA030790/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0076 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 9 hom. )

Consequence

LDLR
NM_000527.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003096

Clinical Significance

Benign reviewed by expert panel P:1U:2B:16

Conservation

PhyloP100: -0.336

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 -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.941-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.941-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00754

AC:

1147

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00193

AC:

485

AN:

250890

Hom.:

AF XY:

0.00141

AC XY:

192

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000768

AC:

1122

AN:

1461238

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

469

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.0268

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00765

AC:

1164

AN:

152236

Hom.:

Cov.:

AF XY:

0.00687

AC XY:

511

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0270

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00488

Hom.:

Bravo

AF:

0.00827

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:2Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:2Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	The NM_000527.5(LDLR):c.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1). BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics. BP4 - No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site MES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64. Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0 B) variant is intronic C) variant is intronic Variant is not predicted to alter splicing. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3%, likely pathogenic based on the integrative in-silico score -
Uncertain significance, 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	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	This variant is associated with the following publications: (PMID: 28145427, 23680767, 10422804, 27884173, 26332594, 27765764, 16250003, 27044878) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2020	- -

Familial hypercholesterolemia

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

May 17, 2017

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.080

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0

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