Variant rs41306974 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000558518.6(LDLR):c.2312-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,549,938 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 31)

Exomes 𝑓: 0.013 ( 151 hom. )

Consequence

LDLR
ENST00000558518.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.749

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 19-11127961-G-A is Benign according to our data. Variant chr19-11127961-G-A is described in ClinVar as [Benign]. Clinvar id is 252278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11127961-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1699/152138) while in subpopulation NFE AF= 0.0173 (1173/67986). AF 95% confidence interval is 0.0164. There are 14 homozygotes in gnomad4. There are 810 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2312-47G>A		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.2312-47G>A		intron_variant		1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1700

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.00877

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0104

AC:

2612

AN:

250328

Hom.:

AF XY:

0.0106

AC XY:

1439

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00853

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.00714

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0132

AC:

18435

AN:

1397800

Hom.:

151

Cov.:

AF XY:

0.0131

AC XY:

9154

AN XY:

699180

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.00921

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.00452

Gnomad4 FIN exome

AF:

0.00764

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0112

AC:

1699

AN:

152138

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

810

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.0155

Gnomad4 ASJ

AF:

0.0132

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00877

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.0114

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

- -

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

-0.85

CADD

Benign

1.1

DANN

Benign

0.55

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