rs14158

Positions:

Variant summary

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

The NM_000527.5(LDLR):c.*52G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,565,802 control chromosomes in the GnomAD database, including 46,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4143 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42451 hom. )

Consequence

LDLR
NM_000527.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.517

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:

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=-0.8).

BP6

Variant 19-11131368-G-A is Benign according to our data. Variant chr19-11131368-G-A is described in ClinVar as [Benign]. Clinvar id is 265910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11131368-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.*52G>A		3_prime_UTR_variant	18/18	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.*52G>A		3_prime_UTR_variant	18/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34515

AN:

151948

Hom.:

4136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.208

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.218

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.228

GnomAD3 exomes

AF:

0.243

AC:

61151

AN:

251262

Hom.:

7866

AF XY:

0.239

AC XY:

32499

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.171

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.218

Gnomad EAS exome

AF:

0.382

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.219

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.241

AC:

340384

AN:

1413734

Hom.:

42451

Cov.:

AF XY:

0.239

AC XY:

168693

AN XY:

706344

show subpopulations

Gnomad4 AFR exome

AF:

0.160

Gnomad4 AMR exome

AF:

0.256

Gnomad4 ASJ exome

AF:

0.215

Gnomad4 EAS exome

AF:

0.399

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.229

Gnomad4 NFE exome

AF:

0.243

Gnomad4 OTH exome

AF:

0.239

GnomAD4 genome

AF:

0.227

AC:

34540

AN:

152068

Hom.:

4143

Cov.:

AF XY:

0.226

AC XY:

16762

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.174

Gnomad4 AMR

AF:

0.239

Gnomad4 ASJ

AF:

0.208

Gnomad4 EAS

AF:

0.383

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.218

Gnomad4 NFE

AF:

0.251

Gnomad4 OTH

AF:

0.227

Alfa

AF:

0.244

Hom.:

8285

Bravo

AF:

0.229

Asia WGS

AF:

0.296

AC:

1028

AN:

3478

EpiCase

AF:

0.232

EpiControl

AF:

0.236

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jun 11, 2018	Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as benign. -
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	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hypercholesterolemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Jun 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.0

DANN

Benign

0.57

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