rs2569538

Positions:

• chr19-11127872-A-G
• chr19-11127872-A-T

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.2312-136A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 786,086 control chromosomes in the GnomAD database, including 312,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57719 hom., cov: 29)
  • Exomes 𝑓: 0.90 (254816 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.38

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-11127872-A-G is Benign according to our data. Variant chr19-11127872-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 252277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11127872-A-G is described in Lovd as [Benign]. Variant chr19-11127872-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2312-136A>G		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2312-136A>G		intron_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132155 AN: 151856 Hom.: 57689 Cov.: 29

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.893

GnomAD4 exome AF: 0.896 AC: 568117 AN: 634110 Hom.: 254816 AF XY: 0.895 AC XY: 308180 AN XY: 344188

Gnomad4 AFR exome AF: 0.796

Gnomad4 AMR exome AF: 0.854

Gnomad4 ASJ exome AF: 0.884

Gnomad4 EAS exome AF: 0.912

Gnomad4 SAS exome AF: 0.862

Gnomad4 FIN exome AF: 0.913

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.894

GnomAD4 genome AF: 0.870 AC: 132241 AN: 151976 Hom.: 57719 Cov.: 29 AF XY: 0.872 AC XY: 64745 AN XY: 74250

Gnomad4 AFR AF: 0.793

Gnomad4 AMR AF: 0.860

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.916

Gnomad4 SAS AF: 0.874

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.893

Alfa AF: 0.902 Hom.: 80941

Bravo AF: 0.863

Asia WGS AF: 0.862 AC: 2998 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

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	-0.92
CADD	Benign	1.1
DANN	Benign	0.14

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: rs2569538; hg19: chr19-11238548;