rs755389753
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_ModeratePS3PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1586+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002230028: Disruption of this splice site has been observed in individuals with hypercholesteremia (PMID:9974426, 23375686, 30710474, 31491741, 35339733). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID:9974426)." and additional evidence is available in ClinVar. The gene LDLR is included in the ClinGen Criteria Specification Registry.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
LDLR
NM_000527.5 splice_donor, intron
NM_000527.5 splice_donor, intron
Scores
4
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.64
Publications
2 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]
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ACMG classification
Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08826946 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PS3
PS3 evidence extracted from ClinVar submissions: SCV002230028: Disruption of this splice site has been observed in individuals with hypercholesteremia (PMID: 9974426, 23375686, 30710474, 31491741, 35339733). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9974426).; SCV002705979: This alteration has also been detected in other FH cohorts (Liguori, 2001; Romano, 2010). This nucleotide position is highly conserved in available vertebrate species. This alteration was reported to result in abnormal splicing, leading to two abnormal mRNA products, one with an in-frame insertion of 22 amino acids, and one with an in-frame deletion of 76 amino acids in the epidermal growth factor precursor homology domain (Bertolini, 1999).
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11113763-G-A is Pathogenic according to our data. Variant chr19-11113763-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | TSL:1 MANE Select | c.1586+1G>A | splice_donor intron | N/A | ENSP00000454071.1 | P01130-1 | |||
| LDLR | TSL:1 | c.1844+1G>A | splice_donor intron | N/A | ENSP00000252444.6 | J3KMZ9 | |||
| LDLR | TSL:1 | c.1586+1G>A | splice_donor intron | N/A | ENSP00000453346.1 | P01130-5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251100 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251100
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457142Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725228 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1457142
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
725228
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33376
American (AMR)
AF:
AC:
0
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26108
East Asian (EAS)
AF:
AC:
0
AN:
39680
South Asian (SAS)
AF:
AC:
0
AN:
86154
European-Finnish (FIN)
AF:
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1107752
Other (OTH)
AF:
AC:
0
AN:
60218
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ExAC
AF:
AC:
1
EpiCase
AF:
EpiControl
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
5
-
-
Hypercholesterolemia, familial, 1 (5)
2
-
-
Familial hypercholesterolemia (2)
1
-
-
Cardiovascular phenotype (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
PhyloP100
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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