rs781362878

Variant names:

• chr19-11113767-G-A
• rs781362878
• NM_000527.5:c.1586+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113767-G-A
• chr19-11113767-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1586+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PS3_Moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PS3_Moderate:-Level 2, PMID 10668928 (Jensen et al., 1999), heterologous cells (COS-7), FACS and CLSM assays, mutant protein retained at ER; <2% LDLR at surface, 2-5% LDL uptake. Overall LDLR activity is below 70% of wild-type activity.-Level 3, PMID 19208450 (Holla et al., 2009), heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays showed skipping of exon 10 (p.Thr454_Gly529del). -Level 3, PMID 10668928 (Jensen et al., 1999), heterozygous patients' Epstein Barr virus transformed lymphocytes, quantitative RT-PCR assays. Mutated transcripts were 47% of total transcripts; from mutated allele: 50% correctly spliced RNA, skipping of exon 10 (p.Thr454_Gly529del) in 25% of RNAs and retention of the first 66 nucleotides from intron 10 (p.Gly529_Phe530insCysValSerThrThrLeuArgAlaAlaGluGlyMetGluGlyAlaGlyArgSerPheArgAsnCys) in 25% of RNAs. LINK:https://erepo.genome.network/evrepo/ui/classification/CA035154/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: LDLR NM_000527.5 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel P:16 U:5
• Conservation: PhyloP100: 9.40
• Publications: 4 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.

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.1586+5G>A		splice_region intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1586+5G>A		splice_region intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1463+5G>A		splice_region 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.1586+5G>A		splice_region intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1844+5G>A		splice_region intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1586+5G>A		splice_region intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250846 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1452200 Hom.: 1 Cov.: 31 AF XY: 0.0000277 AC XY: 20 AN XY: 722982

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1103334

Other (OTH) AF: 0.00 AC: 0 AN: 60064

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	5	-	Hypercholesterolemia, familial, 1 (13)
3	-	-	Familial hypercholesterolemia (3)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Benign	0.71
PhyloP100		9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781362878; hg19: chr19-11224443;