19-11116790-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.1706-69G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,569,414 control chromosomes in the GnomAD database, including 23,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4311 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18979 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.85

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=-0.87).
• BP6: Variant 19-11116790-G-T is Benign according to our data. Variant chr19-11116790-G-T is described in ClinVar as [Benign]. Clinvar id is 251985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116790-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1706-69G>T		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1706-69G>T		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32053 AN: 152038 Hom.: 4298 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.152 AC: 215490 AN: 1417258 Hom.: 18979 AF XY: 0.152 AC XY: 107736 AN XY: 707552

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.211 AC: 32100 AN: 152156 Hom.: 4311 Cov.: 33 AF XY: 0.209 AC XY: 15543 AN XY: 74386

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.181

Alfa AF: 0.0925 Hom.: 151

Bravo AF: 0.220

Asia WGS AF: 0.223 AC: 777 AN: 3478

ClinVar

Significance: 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	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	3 hmz + 28 htz / 125 non-FH individuals -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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	0.18
Dann	Benign	0.66

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: rs7259278; hg19: chr19-11227466; COSMIC: COSV52946963; COSMIC: COSV52946963;