rs139043155
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.798T>A(p.Asp266Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266G) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: -1.19
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 Pathogenic. Variant got 18 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000527.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr19-11106667-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251457.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
?
Variant 19-11106668-T-A is Pathogenic according to our data. Variant chr19-11106668-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 161287.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11106668-T-A is described in Lovd as [Pathogenic]. Variant chr19-11106668-T-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.798T>A | p.Asp266Glu | missense_variant | 5/18 | ENST00000558518.6 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.798T>A | p.Asp266Glu | missense_variant | 5/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:36Uncertain:2Benign:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:21Benign:1
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 09, 2008 | - - |
| Likely benign, criteria provided, single submitter | research | Institute for Integrative and Experimental Genomics, University of Luebeck | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 24, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Oct 30, 2017 | The nucleotide substitution c.798T>A causes an exchange of the amino acid aspartate acid to glutamate at position 266 (p.Asp266Glu, D266E). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1301956, 11810272, 16542394 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jul 06, 2017 | This c.798T>A (p.Asp266Glu) variant has previously been detected in multiple patients with familial hypercholesterolemia [PMID 1301956, 11196104, 25637381, 25487149, 11810272, 16542394, 21310417, also reported as FH Cincinnati-1 (legacy: 245)]. Additional patients with hypercholesterolemia have been reported with variants located at the same amino acid position (p.Asp266Asn, p.Asp266Gly, p.Asp266Tyr and p.Asp266Val). This variant was observed in ten heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/19-11217344-T-A This variant is highly conserved in mammals and computer-based algorithms predict this p.Asp266Glu change to be deleterious. It is thus classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 11, 2023 | Criteria applied: PS4,PM5_STR,PP1_STR,PS3_MOD,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 06, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Sep 10, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Cincinnati-1, 15 to 30% LDLR activity / Software predictions: Damaging - |
| Likely pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 04, 2019 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 07, 2021 | The NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM5_Strong, PM2, PS3_Moderate and PP4) 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: PS4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. PP1_strong - variant segregates with phenotype in over 30 informative meiosis in several families from different laboratories. PM5_strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is met. PM2 - PopMax MAF = 0.00007740 (0.008%) in european non-finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Overall LDLR activity is below 70% of wild-type activity, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Mar 13, 2019 | This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia or early-onset myocardial infarction (PMID: 23375686, 25487149). Functional studies by Hobbs et al. (PMID 1301956) demonstrated that LDL receptor activity in patients with the p.Asp266Glu variant is 15-30% of wild type allele. This change is reported in ClinVar by other clinical laboratories (Variation ID 161287), as well as described as disease causing variant in the Human Disease Mutation Database. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/277250) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.798T>A (p.Asp266Glu) variant on protein function. Based on the available evidence, the c.798T>A (p.Asp266Glu) variant is classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jul 05, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant (also known as p.Asp245Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 266 in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a homozygous carrier has shown that this variant causes a significant decrease of LDLR (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia and is known to be a common cause of disease in the Czech, German and Austrian populations (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760). This variant has been identified in 10/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Asn, p.Asp266Gly, and p.Asp266Val) are considered to be disease-causing (ClinVar variation ID: 226334, 251457, and 251458), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:8Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | LDLR: PP1:Strong, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 27, 2022 | PP1_strong, PP4, PM2, PM5_strong, PS3, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 27, 2021 | The LDLR c.798T>A (p.Asp266Glu) variant has been reported in the published literature in individuals affected with familial hypercholesterolemia (FH) (PMIDs: 33269076 (2021), 26892515 (2016), 23375686 (2013), 22698793 (2012), 20145306 (2010), 16542394 (2006), 15199436 (2004), 10657581 (2000)). In addition, this variant is reported to result in reduced LDLR receptor activity (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.000077 (10/129194 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 19, 2016 | The patient had genetic testing for the familial hypercholesterolemia panel with Ambry Genetics. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): p.Asp266Glu (c.798T>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in more than 20 unrelated cases of familial hypercholesterolemia (not including this patient's family). This variant is also reported in the literature as p.Asp245Glu (c.798T>A). Hobbs, et al. 1992 first reported this variant in his cohort of patients with FH. The patient was diagnosed with hyperlipidemia type 2B (FH), and had 15-30 % of residual LDLR activity. Schmidt, et al. 2000 reported this variant in 16 unrelated index cases in Australia. They were all clinically diagnosed with familial hypercholesterolemia and is one of the most common variants identified in his Australian cohort of 950 index cases. Fouchier SW et al. 2001 identified this variant and a similar variant at the same position, D245N, in his cohort. Brusgaard, et al. 2006 also reported this variant in three individuals who had a clinical diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.998). The aspartic acid at codon 266 is conserved across species, as are some neighboring amino acids. Other variants have been reported in association with disease at this codon (D245N). There are two individuals with variation at codon 266 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 10, 2016). The average coverage at that site in ExAC is 40x. - |
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2022 | Also known as FH Cincinnati-1 and p.D245E; Published functional studies classify D266E as partially transport-defective with LDL receptor activity at 15-30% (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24014831, 25637381, 20145306, 23375686, 25487149, 26036859, 25647241, 1301956, 26892515, 22881376, 15556092, 23064986, 11052664, 11524740, 28008010, 24507775, 27596133, 29083407, 30795984, 31401775, 34426522, 32719484, 33740630, 32041611, 33269076, 34037665, 31447099, 32770674, 33418990, 23833242, 35741760, 33955087, 27824480, 22698793) - |
Familial hypercholesterolemia Pathogenic:4Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 05, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 08, 2020 | Variant summary: LDLR c.798T>A (p.Asp266Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.798T>A has been widely reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Tichy_2012, Goldmann_2010, Duskova_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hobbs_1992). The most pronounced variant effect results in 15%-30% of normal LDL receptor activity. Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic/pathogenic, n=16). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2023 | This missense variant (also known as p.Asp245Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 266 in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a homozygous carrier has shown that this variant causes a significant decrease of LDLR (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia and is known to be a common cause of disease in the Czech, German and Austrian populations (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760). This variant has been identified in 10/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Asn, p.Asp266Gly, and p.Asp266Val) are considered to be disease-causing (ClinVar variation ID: 226334, 251457, and 251458), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 266 of the LDLR protein (p.Asp266Glu). This variant is present in population databases (rs139043155, gnomAD 0.008%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499). This variant is also known as p.Asp245Glu. ClinVar contains an entry for this variant (Variation ID: 161287). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hypercholesterolemia Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Apr 25, 2022 | ACMG categories: PS1,PS4,PM2,PP5,BP1 - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 15, 2020 | The p.Asp266Glu variant (also described as p.Asp245Glu in the literature) has been reported in over 100 individuals with familial hypercholesterolemia (FH; Bertolini 2013 PMID: 23375686, Brænne 2015 PMID: 26036859, Brusgaard 2006 PMID: 16542394, Chmara 2010 PMID: 20145306, Do 2015 PMID: 25487149, Fouchier 2001 PMID: 11810272, Hobbs 1992 PMID: 1301956, Schmidt 2000 PMID: 10657581, Sharifi 2016 PMID: 26892515, Tichý 2012 PMID: 22698793, Weiss 2000 PMID: 11196104) and reportedly segregated with disease in numerous affected relatives from multiple families (Clinvar, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation SCV000540759.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161287) and has been identified in 0.008% (10/129194) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp266Glu variant may impact protein function, resulting in 15-30% LDL receptor activity (Hobbs 1992 PMID: 1301956). Computational prediction tools and conservation analysis suggest that the p.Asp266Glu variant may impact the protein. Another likely pathogenic missense change at the same position (p.Asp266Tyr) has been reported in association to FH (reported as p.Asp245Tyr, Weiss 2000 PMID: 11196104). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM5_Supporting, PM2_Supporting , PP3, PS3_supporting. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2023 | The c.798T>A (p.D266E) alteration is located in coding exon 5 of the LDLR gene. This alteration results from a T to A substitution at nucleotide position 798, causing the aspartic acid (D) at amino acid position 266 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (10/282892) total alleles studied. The highest observed frequency was 0.008% (10/129194) of European (non-Finnish) alleles. This alteration, referred to as D245E, was described in multiple individuals from familial hypercholesterolemia (FH) cohorts, and reduced LDL-R activity was reported in patients' cultured fibroblasts (Hobbs, 1992; Schmidt, 2000; Fouchier, 2001; Brusgaard, 2006). Multiple other alterations at the same codon, c.796G>A (p.D266N), c.796G>C (p.D266H), c.797A>G (p.D266G), c.797A>T (p.D266V), and c.796G>T (p.266Y), have been described in association with FH (Weiss, 2000; Fouchier, 2001; Yu, 2002; Chmara, 2010; Xiang, 2017). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;H
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at K262 (P = 0.1283);Gain of ubiquitination at K262 (P = 0.1283);.;.;Gain of ubiquitination at K262 (P = 0.1283);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at