17-16940415-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1PM5PP5_Very_StrongBP4BS1_Supporting
The NM_012452.3(TNFRSF13B):โc.542C>Aโ(p.Ala181Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,614,040 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181G) has been classified as Likely pathogenic.
Frequency
Genomes: ๐ 0.0049 ( 5 hom., cov: 32)
Exomes ๐: 0.0054 ( 44 hom. )
Consequence
TNFRSF13B
NM_012452.3 missense
NM_012452.3 missense
Scores
2
4
12
Clinical Significance
Conservation
PhyloP100: 0.00700
Genes affected
TNFRSF13B (HGNC:18153): (TNF receptor superfamily member 13B) The protein encoded by this gene is a lymphocyte-specific member of the tumor necrosis factor (TNF) receptor superfamily. It interacts with calcium-modulator and cyclophilin ligand (CAML). The protein induces activation of the transcription factors NFAT, AP1, and NF-kappa-B and plays a crucial role in humoral immunity by interacting with a TNF ligand. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a transmembrane_region Helical; Signal-anchor for type III membrane protein (size 20) in uniprot entity TR13B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_012452.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP5
Variant 17-16940415-G-T is Pathogenic according to our data. Variant chr17-16940415-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-16940415-G-T is described in Lovd as [Likely_pathogenic]. Variant chr17-16940415-G-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.08364344). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00486 (740/152274) while in subpopulation NFE AF= 0.006 (408/68008). AF 95% confidence interval is 0.00552. There are 5 homozygotes in gnomad4. There are 427 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00486 AC: 740AN: 152156Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00533 AC: 1336AN: 250718Hom.: 9 AF XY: 0.00526 AC XY: 713AN XY: 135572
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GnomAD4 exome AF: 0.00544 AC: 7954AN: 1461766Hom.: 44 Cov.: 31 AF XY: 0.00532 AC XY: 3867AN XY: 727176
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GnomAD4 genome 0.00486 AC: 740AN: 152274Hom.: 5 Cov.: 32 AF XY: 0.00574 AC XY: 427AN XY: 74454
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:28Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:12Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Revvity Omics, Revvity | Sep 13, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | TNFRSF13B: PS3, PS4, PP1 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2022 | Commonly occurring variant associated with CVID, observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013); Published functional studies demonstrates the A181E variant introduces a negative charge in the transmembrane domain, which disrupts signaling and impairs B-cell function (Lee et al., 2009); 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: 21850030, 26096648, 19629655, 19779048, 22884984, 27609654, 27123465, 30659808, 31530980, 30843876, 21419480, 19605846, 21547394, 19392801, 22076597, 16007087, 18981294, 23237420, 24051380, 26100089, 17392797, 20156508, 27577878, 16007086, 32581362, 34426522, 30739909, 33046446, 33726816) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 13, 2024 | PP1, PS3, PS4 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital | Jun 26, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2024 | The TNFRSF13B c.542C>A; p.Ala181Glu variant (rs72553883) is reported in the literature in multiple individuals diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013). This variant is also observed in clinically asymptomatic relatives and is found in the Finnish European population with an overall allele frequency of 2.4% (603/24990 alleles, including eight homozygotes) in the Genome Aggregation Database, suggesting it may act as a susceptibility or disease-associated variant, possibly with other genetic and/or environmental factors (Dong 2010). Still, case-control studies demonstrate the p.Ala181Glu variant is significantly enriched in affected individuals (OR >5, p< 0.05) (Pan-Hammarstrom 2007, Dong 2010, Freiberger 2012). Functional characterization of the p.Ala181Glu protein in mice (A144E) and human B-cells indicate disrupted NF-KB signaling and significantly impaired B-cell function (Lee 2009, Fried 2011). Based on available information, the variant is considered to be pathogenic. References: Castigli E et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. Dong X et al. (2010) Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B-A181E mutations in common variable immunodeficiency. Hum Immunol. 71(5):505-11. Freiberger T et al. Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. Hum Immunol. 2012 Nov;73(11):1147-54. Fried A et al. Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jul;128(1):226-228.e1. Martinez-Gallo M et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 Feb;131(2):468-76. Lee J et al. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood. 2009 Sep 10;114(11):2254-62. Pan-Hammarstrom Q et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 Apr;39(4):429-30. Salzer U et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 30, 2022 | - - |
Immunodeficiency, common variable, 2 Pathogenic:10Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | May 02, 2024 | ACMG Criteria: PS3, PS4, PM1, PM3, PP5; Variant was found in heterozygous state - |
| Established risk allele, no assertion criteria provided | research | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TNFRSF13B c.542C>A (p.Ala181Glu) variant (dbSNP: rs72553883) was identified in ClinVar and was classified as pathogenic x9 (ARUP Laboratories, Centre for Mendelian Genomics University Medical Centre Ljubljana, Baylor, Mayo Clinic, AiLife Diagnostics, Mendelics, GeneDx, OMIM) and likely pathogenic x13 (Genetics Services Laboratory Univerisyt of Chicago, Invitae, LabCorp, Institute of Human Genetics University of Leipzig Medical Center, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, CeGaT Center for Human Genetics Tuebingen, Genome Diagnostics Laboratory University Medical Center Utrecht, Genome Diagnostics Laboratory Amsterdam University Medical Center, Diagnostic Laboratory, Department of Genetics University Medical Center Groningen, Joint Genome Diagnostic Labs from Nijmegen and Maastricht Radboudumc and MUMC+, Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC Erasmus Medical Center) in association with common variable immunodeficiency 2/not provided and likely benign by Illumina in association with dominant common variable immune deficiency (Please refer to ClinVar Accession: VCV000005303.37; Variation ID: 5303 for additional information). The variant was observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013) (verbatim: GeneDx, Accession: SCV000321966.7). In a case-control study of 844 individuals with common variable immune deficiency (CVID) and 3924 controls, this variant was found to be a risk factor for development of CVID (OR 5.60, CI 2.99-10.51) (PMID: 17392797). A meta-analysis of 1,439 CVID patients and 3,558 controls showed that this variant is significantly enriched in CVID patients (PMID: 22884984) (verbatim: Invitae, Accession: SCV000649857.5). The variant was identified in control databases in 1540 of 282092 chromosomes (10 homozygous) at a frequency of 0.005459, and was observed at the highest frequency in the European (Finnish) population in 603 of 24990 chromosomes (freq: 0.02413) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A181 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic- risk factor for common variable immunodeficiency. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Jun 17, 2024 | This sequence variant is a single nucleotide substitution (C>A) at position 542 of the coding sequence of the TNFRSF13B gene that results in an alanine to glutamic acid amino acid change at residue 181 of the TACI protein. The 181 residue falls in the transmembrane domain (PMID: 21419480) of the TACI protein. This is a previously reported variant (ClinVar 5303) and is one of the most common variants associated with common variable immune deficiency when in the heterozygous, compound heterozygous, or homozygous states (PMID: 19605846, 23237420, 22884984, 19779048). This variant has also been observed in unaffected individuals (PMID: 23237420, 22884984, 20156508). However, in case-control studies this variant is significantly overrepresented in individuals affected by common variable immune deficiency (PMID: 22884984, 20156508). This variant is present in 2076 of 402874 alleles (0.5153%) in the gnomAD population dataset. Predictions from multiple bioinformatic tools provided conflicting predictions concerning the impact of this amino acid change, and the Ala181 residue at this position is poorly conserved across the vertebrate species examined. In vitro and in vivo studies suggest that this variant significantly reduces downstream signaling (PMID: 21419480, 19605846). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PS3, PS4 - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Nov 08, 2023 | The TNFRSF13B c.542C>A (p.Ala181Glu) variant has been reported in individuals with CVID in the heterozygous, homozygous, and compound heterozygous state with other pathogenic TNFRSF13B variants (Castigli E et al., PMID: 16007086; Martinez-Gallo M et al., PMID: 23237420; Salzer U et al., PMID: 16007087). This variant has been reported in the ClinVar database as a germline variant with discrepant classifications: pathogenic by 7 submitters, likely pathogenic by 8 submitters, variant of uncertain significance by 2 submitters, and likely benign by 1 submitter. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.4% in the European (Finnish) population which is higher than the expected allele frequency for pathogenic TNFRSF13B variants, but case control studies demonstrate the variant is enriched in affected individuals (OR 5.6; Dong X et al., PMID: 20156508; Freiberger T et al., PMID: 22884984; Pan-Hammarstrโโm Q et al., PMID: 17392797). In vitro functional studies indicated that the variant impaired downstream signaling and a murine model was shown to have impaired signaling and function in vivo (Fried AJ et al., PMID: 21419480; Lee JJ et al., PMID: 19605846). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2025 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 181 of the TNFRSF13B protein (p.Ala181Glu). This variant is present in population databases (rs72553883, gnomAD 2.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (PMID: 16007086, 16007087, 20156508). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5303). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF13B protein function. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 19605846, 21419480, 23237420, 24051380). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 14, 2022 | Criteria applied: PS3,PS4 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 10, 2009 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 08, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PP1 supporting - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 10, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Immunoglobulin A deficiency 2 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 29, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 10, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 11, 2020 | ACMG classification criteria: PS3, PS4, PM3, BS2 - |
Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Feb 20, 2022 | TNFRSF13B NM_012452.2 exon 4 p.Ala181Glu (c.542C>A): This variant has been reported in the literature in several individuals with features of immunodeficiency and segregating with disease in families, most often Common variable immune deficiency (CVID) (selected publications:Salzer 2005 PMID:16007087, Pan Hammerstrom 2007 PMID:17392797, Lee 2009 PMID:19605846, Dong 2010 PMID:20156508, Freiberger2012 PMID:22884984, Janzi 2012 PMID:21850030, Marinez-Gallo 2013 PMID:23237420 Romberg 2013 PMID:24051380) and this variant is listed as one of the most common variants identified in patients with CVID. This variant is present in 2.4% (603/24990) of Finnish alelles including 8 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16940415-G-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:5303). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies (including a murine model) suggest that this variant impacts the protein (Lee 2009 PMID 19605846, Fried 2011 PMID:21419480, Martinez-Gallo 2013 PMID:23237420, Romberg 2013 PMID:24051380) potentially through impaired expression and signaling. Of note, this variant has been identified in family members who do not present with disease and is present at a high frequency, including homozygotes, in assumed unaffected individuals suggesting notable reduced penetrance and/or variable expressivity. In summary, data on this variant is highly suspicious for disease, but the presence of conflicting data requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. - |
Common variable immunodeficiency Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2020 | Variant summary: TNFRSF13B c.542C>A (p.Ala181Glu) results in a non-conservative amino acid change in 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 0.0053 in 250818 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 1864 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), suggesting that the variant is benign. However, this variant has been reported in many individuals with Common Variable Immunodeficiency (CVID, examples: Dong_2010, Castigli_2005, Martinez-Gallo_2013, Salzer_2011, Pomar_2009). These data indicate that the variant is likely to be associated with disease. The variant has been reported in CVID patients as heterozygous, homozygous, and in compound heterozygosity with other pathogenic variants in TNFRSF13B. c.542C>A has been shown to segregate with disease in multiple families (example: Castigli_2005), but has also been observed in unaffected family members (example: Martinez-Gallo_2013), indicating reduced penetrance. Different clinical manifestations have been observed in individuals with the variant, even within the same family (example: Dong_2010). The variant was associated with CVID in a case-control study (OR=5.60, CI 2.99-10.51; Pan-Hammarstrom_2007) and a meta-analysis of cases and controls from the literature (Freiberger_2012). In-vitro functional studies indicated that the variant impaired downstream signaling (example-Fried_2011). In addition, a murine model equivalent to the A181E mutation was assessed as having impaired TACI signaling and function in-vivo (Lee_2009). Six ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments of pathogenic/likely pathogenic (n=4, ) uncertain significance (n=1), likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
T
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