rs14158

Variant names:

• chr19-11131368-G-A
• rs14158
• NM_000527.5:c.*52G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11131368-G-A
• chr19-11131368-G-C
• chr19-11131368-G-T

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: -0.517
• Publications: 47 publications found

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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 265910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.*52G>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.*52G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_000527.5	ENSP00000454071.1

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

GnomAD2 exomes AF: 0.243 AC: 61151 AN: 251262 AF XY: 0.239

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 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

African (AFR) AF: 0.160 AC: 5194 AN: 32444

American (AMR) AF: 0.256 AC: 11449 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5553 AN: 25858

East Asian (EAS) AF: 0.399 AC: 15728 AN: 39426

South Asian (SAS) AF: 0.179 AC: 15246 AN: 85284

European-Finnish (FIN) AF: 0.229 AC: 12236 AN: 53396

Middle Eastern (MID) AF: 0.171 AC: 971 AN: 5678

European-Non Finnish (NFE) AF: 0.243 AC: 259960 AN: 1068194

Other (OTH) AF: 0.239 AC: 14047 AN: 58786

GnomAD4 genome AF: 0.227 AC: 34540 AN: 152068 Hom.: 4143 Cov.: 32 AF XY: 0.226 AC XY: 16762 AN XY: 74318

African (AFR) AF: 0.174 AC: 7212 AN: 41496

American (AMR) AF: 0.239 AC: 3646 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1977 AN: 5162

South Asian (SAS) AF: 0.193 AC: 931 AN: 4820

European-Finnish (FIN) AF: 0.218 AC: 2302 AN: 10582

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17039 AN: 67978

Other (OTH) AF: 0.227 AC: 479 AN: 2106

Alfa AF: 0.244 Hom.: 19530

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 11, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as benign. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles -

not provided Benign:2

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:1

Jun 30, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.0
DANN	Benign	0.57
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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