19-11120082-G-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_000527.5(LDLR):c.1846-10G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
LDLR
NM_000527.5 splice_polypyrimidine_tract, intron
NM_000527.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00002065
2
Clinical Significance
Conservation
PhyloP100: -0.629
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
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Variant 19-11120082-G-T is Benign according to our data. Variant chr19-11120082-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 252072.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11120082-G-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1846-10G>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1846-10G>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251482Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135922
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461676Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 727166
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:1Benign:4
Uncertain significance, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Aug 22, 2019 | - - |
Likely benign, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | NM_000527.5(LDLR):c.1846-10G>T variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009643 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP2 - Variant identified in an index case with heterozygous FH phenotype (LDLc = 6.5 mmol/l) and APOB variant p.(Arg3527Gln), classified as Pathogenic by the general ACMG guidelines from Robarts Research Institute. BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -20 to +3 bases of canonical acceptor splicing site MES scores: de novo acceptor = 11.36, authentic acceptor = 9.58. Ratio variant/wt = 1.18. It is above 1.0. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met. Variant has 2 BP evidence codes towards Benign, enough to classify as Likely benign, and only 1 PM evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. - |
Likely benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The c.1846-10G>T variant in LDLR has been reported in at least 1 individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 252072), and has been identified in 0.004595% (13/282890) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368243304). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 252072). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015). - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2017 | Variant summary: The LDLR c.1846-10G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. In Alamut 3/5 splice prediction tools predict significant enhancement effect on the exon 13 acceptor site. In a published study also a slight increase in affinity was predicted for the splicing acceptor site using a different set of in silico tools (Usifo 2012). ESE finder predicts that this variant may affect the binding sites of the splicing factors SRp55, ASF/SF2 and SC35. Another study, using other in silico algorithms for splicing analyses, predicted also a deleterious score for the variant (Wang 2016). These predictions however have not been confirmed by functional studies. This variant was found in 12/277244 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant of interest has been reported in affected individuals (Usifo 2012, Wang 2016), where one of the patients also carried a pathogenic APOB variant c.10580G>A (p.Arg3527Gln), suggesting a possibly non-pathogenic role of variant of interest. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Familial hypercholesterolemia Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 06, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at