chr19-11131457-G-A

Variant names:

• chr19-11131457-G-A
• rs3826810
• NM_000527.5:c.*141G>A

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.*141G>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 0.0567 in 900,160 control chromosomes in the GnomAD database, including 1,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (410 hom., cov: 32)
  • Exomes 𝑓: 0.055 (1394 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.22
• Publications: 20 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 (MetaRNN=0.0017805696).
• BP6: Variant 19-11131457-G-A is Benign according to our data. Variant chr19-11131457-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.*141G>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.*141G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0648 AC: 9855 AN: 152052 Hom.: 402 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0383

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0632 AC: 11782 AN: 186552 AF XY: 0.0642

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0551 AC: 41193 AN: 747990 Hom.: 1394 Cov.: 10 AF XY: 0.0570 AC XY: 22581 AN XY: 396092

African (AFR) AF: 0.110 AC: 2096 AN: 19140

American (AMR) AF: 0.0495 AC: 1825 AN: 36900

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 1462 AN: 21334

East Asian (EAS) AF: 0.112 AC: 3822 AN: 34232

South Asian (SAS) AF: 0.0933 AC: 6487 AN: 69546

European-Finnish (FIN) AF: 0.0313 AC: 1530 AN: 48928

Middle Eastern (MID) AF: 0.0488 AC: 215 AN: 4410

European-Non Finnish (NFE) AF: 0.0456 AC: 21749 AN: 476588

Other (OTH) AF: 0.0544 AC: 2007 AN: 36912

GnomAD4 genome AF: 0.0650 AC: 9884 AN: 152170 Hom.: 410 Cov.: 32 AF XY: 0.0636 AC XY: 4732 AN XY: 74408

African (AFR) AF: 0.108 AC: 4494 AN: 41504

American (AMR) AF: 0.0382 AC: 583 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3472

East Asian (EAS) AF: 0.105 AC: 545 AN: 5166

South Asian (SAS) AF: 0.0920 AC: 444 AN: 4826

European-Finnish (FIN) AF: 0.0278 AC: 295 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3044 AN: 68016

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0551 Hom.: 491

Bravo AF: 0.0677

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0433 AC: 167

ExAC AF: 0.0533 AC: 6233

Asia WGS AF: 0.0620 AC: 218 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

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. -

Sep 25, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%), this variant is classified as likely benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	11
DANN	Benign	0.47
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0018	T
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.32	N
Sift	Pathogenic	0.0	D
Vest4		0.099
GERP RS		-2.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=97/3	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: rs3826810; hg19: chr19-11242133; COSMIC: COSV52942248; COSMIC: COSV52942248;