rs14158

chr19-11131368-G-Achr19-11131368-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.517

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]

ACMG classification

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	UniProt
LDLR	NM_000527.5	c.*52G>A		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*52G>A		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34515 AN: 151948 Hom.: 4136 Cov.: 32

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

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.: 25 AF XY: 0.239 AC XY: 168693 AN XY: 706344

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.: 32 AF XY: 0.226 AC XY: 16762 AN XY: 74318

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:5

Revision: criteria provided, multiple submitters, no conflicts

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	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	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	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2018

- -

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

Other links and lift over

dbSNP: rs14158; hg19: chr19-11242044; COSMIC: COSV52943415; COSMIC: COSV52943415;