rs13306513

Positions:

• chr19-11107550-G-A
• chr19-11107550-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000527.5(LDLR):​c.940+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,597,708 control chromosomes in the GnomAD database, including 2,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (174 hom., cov: 31)
  • Exomes 𝑓: 0.050 (2112 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.271

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-11107550-G-A is Benign according to our data. Variant chr19-11107550-G-A is described in ClinVar as [Benign]. Clinvar id is 523739.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11107550-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.940+36G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.940+36G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 5946 AN: 152026 Hom.: 172 Cov.: 31

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0334

GnomAD3 exomes AF: 0.0557 AC: 13895 AN: 249668 Hom.: 484 AF XY: 0.0576 AC XY: 7773 AN XY: 134966

Gnomad AFR exome AF: 0.00871

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.0935

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0496 AC: 71669 AN: 1445564 Hom.: 2112 Cov.: 32 AF XY: 0.0514 AC XY: 36978 AN XY: 719114

Gnomad4 AFR exome AF: 0.00749

Gnomad4 AMR exome AF: 0.0547

Gnomad4 ASJ exome AF: 0.0676

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0946

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0487

GnomAD4 genome AF: 0.0391 AC: 5948 AN: 152144 Hom.: 174 Cov.: 31 AF XY: 0.0404 AC XY: 3004 AN XY: 74358

Gnomad4 AFR AF: 0.00949

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0681

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0953

Gnomad4 FIN AF: 0.0286

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0420 Hom.: 170

Bravo AF: 0.0386

Asia WGS AF: 0.0600 AC: 209 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	research	Iberoamerican FH Network	Mar 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.71
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: rs13306513; hg19: chr19-11218226; COSMIC: COSV52946515; COSMIC: COSV52946515;