rs72658868

Positions:

• chr19-11128126-C-A
• chr19-11128126-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000527.5(LDLR):​c.2389+41C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,575,856 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0098 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (60 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.04

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-11128126-C-A is Benign according to our data. Variant chr19-11128126-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252310.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr19-11128126-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00984 (1498/152250) while in subpopulation AFR AF= 0.0156 (648/41548). AF 95% confidence interval is 0.0146. There are 11 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2389+41C>A		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2389+41C>A		intron_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1493 AN: 152132 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00851

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00814 AC: 2040 AN: 250664 Hom.: 14 AF XY: 0.00820 AC XY: 1112 AN XY: 135614

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.00867 AC: 12342 AN: 1423606 Hom.: 60 Cov.: 27 AF XY: 0.00871 AC XY: 6188 AN XY: 710356

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00317

Gnomad4 EAS exome AF: 0.000582

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00837

GnomAD4 genome AF: 0.00984 AC: 1498 AN: 152250 Hom.: 11 Cov.: 31 AF XY: 0.00998 AC XY: 743 AN XY: 74446

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00998

Gnomad4 NFE AF: 0.00851

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.00925

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.17
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72658868; hg19: chr19-11238802;