rs3745677

chr19-11100401-G-Achr19-11100401-G-Cchr19-11100401-G-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.190+56G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,540,584 control chromosomes in the GnomAD database, including 3,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (851 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3089 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.720

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=-0.9).
• BP6: Variant 19-11100401-G-A is Benign according to our data. Variant chr19-11100401-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 251053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11100401-G-A is described in Lovd as [Benign]. Variant chr19-11100401-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.190+56G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.190+56G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14073 AN: 151898 Hom.: 853 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.0845

GnomAD4 exome AF: 0.0640 AC: 88813 AN: 1388568 Hom.: 3089 Cov.: 22 AF XY: 0.0627 AC XY: 43510 AN XY: 693534

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0546

Gnomad4 ASJ exome AF: 0.0514

Gnomad4 EAS exome AF: 0.0806

Gnomad4 SAS exome AF: 0.0249

Gnomad4 FIN exome AF: 0.0751

Gnomad4 NFE exome AF: 0.0633

Gnomad4 OTH exome AF: 0.0659

GnomAD4 genome AF: 0.0926 AC: 14083 AN: 152016 Hom.: 851 Cov.: 32 AF XY: 0.0897 AC XY: 6668 AN XY: 74318

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0594

Gnomad4 ASJ AF: 0.0478

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.0258

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0652

Gnomad4 OTH AF: 0.0826

Alfa AF: 0.0329 Hom.: 20

Bravo AF: 0.0958

Asia WGS AF: 0.0450 AC: 157 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:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.40
Dann	Benign	0.53

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: rs3745677; hg19: chr19-11211077; COSMIC: COSV52942256; COSMIC: COSV52942256;