rs121908030
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM3PP3PP4PS3_ModeratePS4PP1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 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:PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.883.It is above 0.75, so PP3 is Met.PS3_moderate - 2 Level 2 assays performed by different labs:PMID 2088165:Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity.PMID 6438436:Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity.2 Level 3 assays performed by different labs:PMID 4061492:Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activityPMID 6438436:Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met.PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID:21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID:23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID:17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID:12436241), so PS4 is Met.PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met.PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met.PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023792/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 9.81
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 16 ACMG points.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.910G>A | p.Asp304Asn | missense_variant | 6/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.910G>A | p.Asp304Asn | missense_variant | 6/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes 0.0000527 AC: 8AN: 151924Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251318Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135822
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:11
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 10, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 10, 2018 | This c.910G>A (p.Asp304Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9664576, 11810272, 12436241, 21418584, 21310417) and is extremely rare in the general population. Functional studies have shown that the mutant LDLR protein retains only 5-15% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). This c.910G>A (p.Asp304Asn) variant in the LDLR gene is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant (also known as p.Asp283Asn in the mature protein and as FH Denver-2) replaces aspartic acid with asparagine at codon 304 in the LDLR type A repeat 7 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using fibroblasts from patients with homozygous familial hypercholesterolemia have shown that this variant causes a significant reduction in LDLR activity (PMID: 1301956, 6438436). Another in-vitro functional study has shown that this variant causes in increase in LDLR retention in the endoplasmic reticulum (PMID: 11939787). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 4061491, 9664576, 11810272, 17094996, 21418584, 23064986, 34037665). This variant has also been observed in compound heterozygous state in multiple individuals affected with homozygous familial hypercholesterolemia (PMID: 4061491, 17094996, 27678436, 31048103), indicating that this variant contributes to disease. This variant has been identified in 3/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp304Glu and p.Asp304Tyr, are considered to be disease-causing (ClinVar variation ID: 226336 and 251517), 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, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| 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 | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Dec 17, 2021 | The NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 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: PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.883. It is above 0.75, so PP3 is Met. PS3_moderate - 2 Level 2 assays performed by different labs: PMID 2088165: Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity. PMID 6438436: Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity. 2 Level 3 assays performed by different labs: PMID 4061492: Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activity PMID 6438436: Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity ---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met. PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PS4 is Met. PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met. PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met. PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1988 | - - |
Familial hypercholesterolemia Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 304 of the LDLR protein (p.Asp304Asn). This variant is present in population databases (rs121908030, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2088165, 9664576, 11810272, 12436241, 21418584, 22698793). This variant is also known as Denver-2 and D283N. ClinVar contains an entry for this variant (Variation ID: 3692). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956). This variant disrupts the p.Asp304 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 17094996). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2020 | Variant summary: LDLR c.910G>A (p.Asp304Asn) results in a conservative amino acid change located in the LDL-receptor class A7 domain (Guo_2019) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD and publication data). c.910G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Hobbs_1990, Al-Khateeb_2011, Luirink_2019). 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 and variant effect results in 5-15 % of normal activity (Hobbs_1992). Additionally, other variants at this codon (p.D304E/H/Y/V) have been reported in individuals with Familial Hypercholesterolemia and are considered as likely pathogenic/pathogenic (HGMD database). This suggests that the asparagine at codon 304 of the LDLR protein is critical for protein function. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (5x) and likely pathogenic (4x). 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 03, 2023 | This missense variant (also known as p.Asp283Asn in the mature protein and as FH Denver-2) replaces aspartic acid with asparagine at codon 304 in the LDLR type A repeat 7 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using fibroblasts from patients with homozygous familial hypercholesterolemia have shown that this variant causes a significant reduction in LDLR activity (PMID: 1301956, 6438436). Another in-vitro functional study has shown that this variant causes in increase in LDLR retention in the endoplasmic reticulum (PMID: 11939787). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 4061491, 9664576, 11810272, 17094996, 21418584, 23064986, 34037665). This variant has also been observed in compound heterozygous state in multiple individuals affected with homozygous familial hypercholesterolemia (PMID: 4061491, 17094996, 27678436, 31048103), indicating that this variant contributes to disease. This variant has been identified in 3/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp304Glu and p.Asp304Tyr, are considered to be disease-causing (ClinVar variation ID: 226336 and 251517), 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, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 05, 2021 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 05, 2019 | The frequency of this variant in the general population, 0.00012 (3/24946 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant was identified in multiple individuals affected with hypercholesterolemia (PMID: 11810272 (2001), 12436241 (2002), 21418584 (2011), 22698793 (2012), 23064986 (2012), 24507775 (2014), 33740630 (2021), 34037665 (2021)). The variant has also been reported as compound heterozygous with another pathogenic variant in children with a severe presentation (PMID: 27678436 (2016), 30795984 (2019)). Functional studies of homozygous cultured fibroblasts showed a retention of only 5-15% LDLR activity (PMID: 1301956 (1992)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate significantly reduced LDL receptor activity compared to wild type (Hobbs et al., 1990; Hobbs et al., 1992); Also known as FH Denver-2 and p.D283N; This variant is associated with the following publications: (PMID: 2318961, 12436241, 31447099, 25637381, 25487149, 24507775, 2088165, 9664576, 11810272, 17094996, 21418584, 22698793, 34037665, 30795984, 1301956, 33740630, 32719484) - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 06, 2018 | The p.Asp304Asn variant in LDLR (also described as p.Asp283Asn in the literature ) has been reported in at least 14 individuals (in at least 1 in the homozygous state and at least 13 in the heterozygous state) with familial hypercholesterol emia (FH; Hobbs 1990, Callis 1998, Fouchier 2001, Ansellem 2002, Al-Khateeb 2011 , Tichy 2012, Do 2015). In vitro functional studies provide some evidence that t he p.Asp304Asn variant may impact protein function (Hobbs 1990). This variant ha s also been reported by other clinical laboratories in ClinVar (Variation ID: 36 92) and has been identified in 3/24012 African chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908030). Thi s frequency is consistent with the frequency of FH in the general population. Co mputational prediction tools and conservation analysis suggest that the p.Asp304 Asn variant may impact the protein. In addition, four other variants at this pos ition have been reported in individuals with FH (HGMD database, Stenson 2017), w ith at least one classified as likely pathogenic or pathogenic, suggesting that changes at this position are not tolerated. In summary, this variant meets crit eria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general po pulation, the presence of a different pathogenic variant at the same codon, and functional and computational evidence. ACMG/AMP Criteria applied (Richards 2015) : PS4; PM2; PM5; PP3; PS3_Supporting. - |
Hypercholesterolemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
LDLR-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2024 | The LDLR c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant (also known as D283N) has been reported in heterozygous state to be causative for familial hypercholesterolemia (Callis et al. 1998. PubMed ID: 9664576; Fouchier et al. 2001. PubMed ID: 11810272; Amsellem et al. 2002. PubMed ID: 12436241; Luirink et al. 2019. PubMed ID: 30795984). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2021 | The p.D304N pathogenic mutation (also known as c.910G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 910. The aspartic acid at codon 304 is replaced by asparagine, an amino acid with highly similar properties. This mutation (also referred to as p.D283N and Denver-2) has been reported in numerous familial hypercholesterolemia (FH) cohorts (Callis M et al. Mol. Cell. Probes. 1998;12:149-52; Fouchier SW et al. Hum. Genet. 2001;109:602-15; Amsellem S et al. Hum. Genet. 2002;111:501-10; Tosi I et al. Atherosclerosis. 2007;194:102-11; Al-Khateeb A et al. BMC Med. Genet. 2011;12:40; Ahmad Z et al. Circ Cardiovasc Genet. 2012;5:666-75). It has also been described in the homozygous state in an individual whose LDL receptor activity was 5-15% of normal activity and in the compound heterozygous state with the likely pathogenic alteration LDLR p.E101K in an individual with homozygous FH (Bilheimer DW et al. Am. J. Med. Genet. 1985;22:593-8; Khoo KL et al. J Clin Lipidol. 2016;10:1188-94). Functional studies suggest this mutation results in defective transport of the LDLR protein (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Li Y et al. Biochemistry. 2002;41:4921-8). In addition, three other alterations affecting the same codon (p.D304V, p.D304E, and p.D304Y) have been associated with FH (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Loux N et al. Hum. Mutat. 1992;1:325-32; Lombardi MP et al. Genet. Test. 2006;10:77-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.;M
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T;D;D
Sift4G
Benign
T;T;T;T;T;T
Polyphen
P;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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