Variant 19-11131239-A-G 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.2548-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,609,990 control chromosomes in the GnomAD database, including 179,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13268 hom., cov: 32)

Exomes 𝑓: 0.47 ( 166177 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.486

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:

LDLR (HGNC:):

LDLR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 19-11131239-A-G is Benign according to our data. Variant chr19-11131239-A-G is described in ClinVar as [Benign]. Clinvar id is 252355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11131239-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2548-42A>G		intron_variant		ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2548-42A>G		intron_variant		1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60356

AN:

151928

Hom.:

13273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.465

Gnomad ASJ

AF:

0.470

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.468

Gnomad FIN

AF:

0.525

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.482

Gnomad OTH

AF:

0.418

GnomAD3 exomes

AF:

0.448

AC:

112489

AN:

251028

Hom.:

26138

AF XY:

0.455

AC XY:

61722

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.469

Gnomad ASJ exome

AF:

0.485

Gnomad EAS exome

AF:

0.315

Gnomad SAS exome

AF:

0.464

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.456

GnomAD4 exome

AF:

0.473

AC:

689913

AN:

1457944

Hom.:

166177

Cov.:

AF XY:

0.474

AC XY:

343966

AN XY:

725604

show subpopulations

Gnomad4 AFR exome

AF:

0.185

Gnomad4 AMR exome

AF:

0.470

Gnomad4 ASJ exome

AF:

0.487

Gnomad4 EAS exome

AF:

0.280

Gnomad4 SAS exome

AF:

0.468

Gnomad4 FIN exome

AF:

0.509

Gnomad4 NFE exome

AF:

0.488

Gnomad4 OTH exome

AF:

0.458

GnomAD4 genome

AF:

0.397

AC:

60370

AN:

152046

Hom.:

13268

Cov.:

AF XY:

0.400

AC XY:

29739

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.197

Gnomad4 AMR

AF:

0.464

Gnomad4 ASJ

AF:

0.470

Gnomad4 EAS

AF:

0.296

Gnomad4 SAS

AF:

0.467

Gnomad4 FIN

AF:

0.525

Gnomad4 NFE

AF:

0.482

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.470

Hom.:

30557

Bravo

AF:

0.382

Asia WGS

AF:

0.321

AC:

1117

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:3

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Benign, criteria provided, single submitter	research	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.27

DANN

Benign

0.64

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