rs13306501

Variant names:

• chr19-11128132-G-A
• rs13306501
• NM_000527.5:c.2389+47G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.2389+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0548 in 1,540,490 control chromosomes in the GnomAD database, including 2,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (416 hom., cov: 31)
  • Exomes 𝑓: 0.054 (2311 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.797
• Publications: 6 publications found

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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-11128132-G-A is Benign according to our data. Variant chr19-11128132-G-A is described in ClinVar as Benign. ClinVar VariationId is 431551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2389+47G>A		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2389+47G>A		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2266+47G>A		intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2389+47G>A		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2647+47G>A		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2389+47G>A		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10060 AN: 151972 Hom.: 412 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0941

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0632 AC: 15822 AN: 250258 AF XY: 0.0638

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0461

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0535 AC: 74296 AN: 1388400 Hom.: 2311 Cov.: 24 AF XY: 0.0553 AC XY: 38396 AN XY: 694920

African (AFR) AF: 0.109 AC: 3488 AN: 32120

American (AMR) AF: 0.0513 AC: 2288 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1756 AN: 25726

East Asian (EAS) AF: 0.113 AC: 4434 AN: 39330

South Asian (SAS) AF: 0.0981 AC: 8332 AN: 84922

European-Finnish (FIN) AF: 0.0419 AC: 2214 AN: 52794

Middle Eastern (MID) AF: 0.0578 AC: 325 AN: 5620

European-Non Finnish (NFE) AF: 0.0462 AC: 48246 AN: 1045212

Other (OTH) AF: 0.0554 AC: 3213 AN: 58048

GnomAD4 genome AF: 0.0663 AC: 10084 AN: 152090 Hom.: 416 Cov.: 31 AF XY: 0.0656 AC XY: 4874 AN XY: 74340

African (AFR) AF: 0.107 AC: 4458 AN: 41498

American (AMR) AF: 0.0382 AC: 583 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3470

East Asian (EAS) AF: 0.105 AC: 544 AN: 5160

South Asian (SAS) AF: 0.0939 AC: 450 AN: 4790

European-Finnish (FIN) AF: 0.0400 AC: 424 AN: 10600

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3145 AN: 67996

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0608 Hom.: 64

Bravo AF: 0.0681

Asia WGS AF: 0.0650 AC: 226 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.53
DANN	Benign	0.73
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13306501; hg19: chr19-11238808;