rs10423288

chr19-11105170-T-C

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.314-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,610,442 control chromosomes in the GnomAD database, including 1,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (484 hom., cov: 33)
  • Exomes 𝑓: 0.026 (1445 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.566

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=-0.81).
• BP6: Variant 19-11105170-T-C is Benign according to our data. Variant chr19-11105170-T-C is described in ClinVar as [Benign]. Clinvar id is 265898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105170-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.314-50T>C		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.314-50T>C		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9118 AN: 152066 Hom.: 478 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0523

GnomAD3 exomes AF: 0.0553 AC: 13502 AN: 244044 Hom.: 764 AF XY: 0.0491 AC XY: 6536 AN XY: 133186

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.0569

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0264 AC: 38536 AN: 1458258 Hom.: 1445 Cov.: 33 AF XY: 0.0263 AC XY: 19086 AN XY: 725562

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0523

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0327

GnomAD4 genome AF: 0.0602 AC: 9154 AN: 152184 Hom.: 484 Cov.: 33 AF XY: 0.0608 AC XY: 4528 AN XY: 74414

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0560

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0508

Alfa AF: 0.0482 Hom.: 100

Bravo AF: 0.0703

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	5/95 non-FH individuals -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.74
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10423288; hg19: chr19-11215846; COSMIC: COSV52943549; COSMIC: COSV52943549;