rs376607329
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4_ModeratePS3PS2PP2PP1PM1
This summary comes from the ClinGen Evidence Repository: The c.794G>A p.Arg265Gln variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's:26957, 21766, 506381, 28338; ClinVar SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). The variant has been reported in the literature to segregate with clinical features of a RASopathy in at least 3 family members (PP1; APHP-Robert Debré Hospital internal data; GTR ID: 28338). The p.Arg265Gln variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR Lab ID: 26957, 21766, 506381, 28338; SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). In vitro functional studies provide some evidence that the p.Arg265Gln variant may impact protein function (PS3; PMID 28074573). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1, PS4_Moderate, PS3, PM1, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234739/MONDO:0018997/004
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
PTPN11
NM_002834.5 missense
NM_002834.5 missense
Scores
12
6
2
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | c.794G>A | p.Arg265Gln | missense_variant | 7/16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.794G>A | p.Arg265Gln | missense_variant | 7/16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.794G>A | p.Arg265Gln | missense_variant | 7/15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 151900Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:38
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Noonan syndrome 1 Pathogenic:15
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 15, 2022 | ACMG classification criteria: PS2 strong, PS3 strong, PS4 moderated, PM1 moderated, PP1 supporting, PP2 supporting - |
| Pathogenic, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PS3_Moderate+PS4+PS2_VeryStrong - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | May 26, 2015 | Pathogenic mutations in the PTPN11 gene have been reported to cause Noonan syndrome. This de novo mutation in PTPN11 gene is likely involved in the development delay of this young patient. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Apr 05, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Mar 17, 2023 | This sequence variant is a single nucleotide substitution (G>A) at coding nucleotide position 794 of the PTPN11 gene which results in an arginine to glutamine amino acid change at residue 265 in the PTPN11 protein. This is a previously reported variant (ClinVar) which has been observed as a de novo or familial variant in multiple individuals with Noon syndrome (PMID: 25862627, 28074573). This variant is rare in the gnomAD control population dataset (8/247274 alleles or 0.003%). Multiple bioinformatic tools predict that this glutamic acid to glutamine amino acid change is likely to be damaging, and arginine is conserved at this protein position in all vertebrate species examined. Altering the Arg265 amino increases phosphatase activity in vitro (PMID: 28074573), and the Arg265 residue is part of a salt bridge with Glu76 (PMID: 21365683). This variant has been classified as Pathogenic by the ClinGen RASopathy Expert Panel (Accession: SCV000616412.3). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM1, PP2, PS2, PS3, PS4 - |
| Likely pathogenic, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 16, 2024 | PS4, PM1, PM2, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Noonan syndrome. (PMID:32233106). - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | May 13, 2020 | ACMG codes:PS3, PP3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2+v3: 13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygotes, 0 homozygotes). (I) 0501 - The missense variant is consistently predicted to be damaging by multiple in silico tools and is highly conserved. (SP) 0600 - This variant is located in the tyrosine-protein phosphatase (PTP) domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals and has been classified as pathogenic by an expert panel (Clinvar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Ectopic expression of p.(Arg265Gln) variant in HEK293 cells promotes enhanced ERK phosphorylation by perturbing the autoinhibitory interaction between the SH2 and PTP domains (PMID: 28074573). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Provincial Medical Genetics Program of British Columbia, University of British Columbia | Jan 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Aug 27, 2024 | - - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2021 | Published functional studies demonstrate that R265Q enhances ERK phosphorylation, supporting an activating role for R265Q on the MAPK signaling cascade (Pannone et al., 2017); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27353043, 29493581, 32233106, 28074573, 30602027, 31172509, 16053901, 9491886, 11992261, 34006472, 32719394) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Sep 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 17, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 17, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 07, 2023 | The PTPN11 c.794G>A; p.Arg265Gln variant (rs376607329) is reported in the literature in multiple individuals affected with Noonan syndrome (Chan 2006, Pannone 2017). This variant is also reported in ClinVar (Variation ID: 40522). This variant is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.814). Additionally, this codon is considered to be a hotspot by the ClinGen RASopathy expert panel (Gelb 2018). Functional analyses of the variant protein show gain of function (Pannone 2017), and structural studies show that arginine 265 is likely a critical mediator of interactions between the catalytic PTP domain and the regulatory N-terminal SH2 domain (Darian 2011, Hof 1998). Based on available information, this variant is considered to be pathogenic. References: Chan D et al. A clinical and molecular study of 51 Chinese families with Noonan syndrome. Hk J Pediatr (New Series). 2006 11:290-296. Darian E et al. Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase. Proteins. 2011 79(5):1573-88. PMID: 21365683. Gelb BD et al. ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. Genet Med. 2018 Nov;20(11):1334-1345. PMID: 29493581. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 92(4): 441-450. PMID: 9491886. Pannone L et al. Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. Hum Mutat. 2017 Apr;38(4):451-459. PMID: 28074573. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | PTPN11: PM5, PS2:Moderate, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
LEOPARD syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 25, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2023 | - - |
Metachondromatosis Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2023 | - - |
PTPN11-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2024 | The PTPN11 c.794G>A variant is predicted to result in the amino acid substitution p.Arg265Gln. This variant has been reported in multiple unrelated individuals with Noonan syndrome and was shown to be a de novo event in at least two cases (Fokstuen et al. 2016. PubMed ID: 27353043; Pannone et al. 2017. PubMed ID: 28074573). It has also been reported in an individual with isolated short stature (Freire et al. 2019. PubMed ID: 30602027) and reported to segregate in multiple individuals from a single family with a Noonan-like presentation; however cardiac features were not present in all members (Ranza et al. 2020. PubMed ID: 32233106, Family A). Pathogenic variants in PTPN11 act in a gain-of-function manner by causing an upregulation of the RAS pathway. Consistent with this mechanism, functional studies demonstrated the p.Arg265Gln variant leads to elevated levels of ERK phosphorylation (Pannone et al. 2017. PubMed ID: 28074573). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and multiple clinical labs have interpreted this variant as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40522/). This variant is interpreted as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | May 09, 2018 | - - |
Noonan syndrome Pathogenic:2
| Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.794G>A p.Arg265Gln variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's:26957, 21766, 506381, 28338; ClinVar SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). The variant has been reported in the literature to segregate with clinical features of a RASopathy in at least 3 family members (PP1; APHP-Robert Debré Hospital internal data; GTR ID: 28338). The p.Arg265Gln variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR Lab ID: 26957, 21766, 506381, 28338; SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). In vitro functional studies provide some evidence that the p.Arg265Gln variant may impact protein function (PS3; PMID 28074573). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1, PS4_Moderate, PS3, PM1, PP2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 29, 2015 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 09, 2022 | This variant has been reported in the literature and in ClinVar in numerous patients with features consistent with or suggestive of a RASopathy; this includes as de novo in several instances, and it has been shown to segregate with disease in many similarly affected family members (Selected publications: Pannone 2017 PMID: 28074573; Qiao 2020 PMID: 32719394; Ranza 2020 PMID: 32233106; Sentchordi-Montané 2021 PMID: 34516402; ClinVar Variation ID: 40522). It is present in the Genome Aggregation Database (Highest reported MAF: 0.006% [7/110252]; https://gnomad.broadinstitute.org/variant/12-112910785-G-A?dataset=gnomad_r2_1). This has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VCEP) (ClinVar Variation ID: 40522). Of note, this variant appears to be associated with a milder or even potentially distinct phenotype compared to what is typically seen in individuals with pathogenic variants in this gene (Gelb 2018 PMID: 29493581; Ranza 2020 PMID: 32233106; Sentchordi-Montané 2021 PMID: 34516402). Functional studies have suggested that this variant impacts the encoded protein and one or more of its signaling pathways (Pannone 2017 PMID: 28074573; Ranza 2020 PMID: 32233106). The ClinGen RASopathy VCEP concluded that this residue is functionally important and is considered a mutational hotspot; additionally, missense variation in the PTPN11 gene is a very common mechanism of disease (Gelb 2018 PMID: 29493581). Evolutionary conservation and computational prediction tools support that this variant is likely to impact the protein. In summary, this variant is classified as pathogenic. - |
RASopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2023 | Variant summary: PTPN11 c.794G>A (p.Arg265Gln) results in a conservative amino acid change located in the Tyrosine-specific protein phosphatase, PTPase domain (IPR000242) 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 3.2e-05 in 247274 control chromosomes (gnomAD). c.794G>A has been reported in the literature in individuals affected with Noonan Syndrome and in at least one individual the variant was observed to be de novo (examples: Forkstuen_2016, Pannone_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that R265Q enhances ERK phosphorylation supporting an activating role on MAPK signaling (Pannone_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27353043, 28074573). Twenty three submitters (including ClinGen RASopathy Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 265 of the PTPN11 protein (p.Arg265Gln). This variant is present in population databases (rs376607329, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 27353043, 28074573). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40522). 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 PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 28074573). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2022 | The p.R265Q pathogenic mutation (also known as c.794G>A), located in coding exon 7 of the PTPN11 gene, results from a G to A substitution at nucleotide position 794. The arginine at codon 265 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been detected in multiple individuals with Noonan syndrome, including some de novo cases (van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). Arginine 265 is located in the protein tyrosine phosphatase domain of the PTPN11 protein and forms ionic interaction with glutamate 76 in the SRC-2 homology 2 (N-SH2) domain (Darian E et al. Proteins, 2011 May;79:1573-88; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). Based on our internal structural analysis, this mutation disrupts the very sensitive interface between these two domains, leading to impaired inhibition (Hof P et al. Cell, 1998 Feb;92:441-50; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63). A functional study also demonstrated that R265Q perturbs the autoinhibitory interaction between the two domains and enhances the function of the PTPN11 protein (Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Benign
T;T;T
Polyphen
D;D;.
Vest4
MVP
MPC
1.1
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