chr17-16940415-G-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_StrongBP4BS1_SupportingBS2
The NM_012452.3(TNFRSF13B):c.542C>A(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181V) has been classified as Uncertain significance.
Frequency
Consequence
NM_012452.3 missense
Scores
Clinical Significance
Conservation
Publications
- immunodeficiency, common variable, 2Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, G2P, Ambry Genetics
- common variable immunodeficiencyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_012452.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TNFRSF13B | NM_012452.3 | MANE Select | c.542C>A | p.Ala181Glu | missense | Exon 4 of 5 | NP_036584.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TNFRSF13B | ENST00000261652.7 | TSL:1 MANE Select | c.542C>A | p.Ala181Glu | missense | Exon 4 of 5 | ENSP00000261652.2 | ||
| TNFRSF13B | ENST00000583789.1 | TSL:1 | c.404C>A | p.Ala135Glu | missense | Exon 3 of 4 | ENSP00000462952.1 | ||
| TNFRSF13B | ENST00000579009.1 | TSL:6 | n.648C>A | non_coding_transcript_exon | Exon 1 of 1 |
Frequencies
GnomAD3 genomes 0.00486 AC: 740AN: 152156Hom.: 5 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00533 AC: 1336AN: 250718 AF XY: 0.00526 show subpopulations
GnomAD4 exome AF: 0.00544 AC: 7954AN: 1461766Hom.: 44 Cov.: 31 AF XY: 0.00532 AC XY: 3867AN XY: 727176 show subpopulations
Age Distribution
GnomAD4 genome 0.00486 AC: 740AN: 152274Hom.: 5 Cov.: 32 AF XY: 0.00574 AC XY: 427AN XY: 74454 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:12Uncertain:1
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 (PMID: 23237420, 19605846); Published functional studies demonstrates the A181E variant introduces a negative charge in the transmembrane domain, which disrupts signaling and impairs B-cell function (PMID: 19605846); 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, 34975878, 30659808, 31530980, 30843876, 34922003, 21419480, 21547394, 19392801, 22076597, 16007087, 18981294, 24051380, 26100089, 17392797, 20156508, 27577878, 16007086, 32581362, 34426522, 30739909, 33046446, 35293001, 35686370, 35570134, 35874679, 35753512, 33726816, 34441032, 19605846, 23237420, 39563277, 39678379, 38282561)
TNFRSF13B: PS3, PS4, PP1
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.
PP1, PS3, PS4
Immunodeficiency, common variable, 2 Pathogenic:12Other:1
The variant is observed in the gnomAD v4.0.0 dataset (total allele frequency: 0.539%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 19605846). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005303 /PMID: 16007087 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17392797, 20156508, 22884984). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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
This variant is classified as Risk allele. Evidence in support of pathogenic classification: This variant has strong previous evidence for being a risk allele in unrelated individuals. It is one of the most common variants in TNFRSF13B associated with common variable immunodeficiency, in both monoallelic and biallelic states (PMIDs: 20156508, 27123465, 34441032), and it is well reported as likely pathogenic/pathogenic in ClinVar. It has also been reported in asymptomatic individuals (PMIDs: 21419480, 32375967); This variant has moderate functional evidence supporting abnormal protein function. Functional studies using transfected cells showed this variant results in a loss of NFkB and NF-AT activation (PMID: 21419480). Additional information: Variant is predicted to result in a missense amino acid change from alanine to glutamic acid; This variant is heterozygous; This gene is associated with both recessive and dominant disease (OMIM); Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v4: 8596 heterozygote(s), 49 homozygote(s)); Alternative amino acid change(s) at the same position are present in gnomAD (Highest alelle count: v4: 21 heterozygote(s), 0 homozygote(s)); Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Ala181Val) has been reported in three individuals with multiple myeloma or monoclonal gammopathy of undetermined significance (PMID: 33751038); Variant is located in the annotated transmembrane domain (PMID: 21419480); Missense variant with inconclusive in silico prediction and/or uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 2 (MIM#240500) and immunoglobulin A deficiency 2 (MIM#609529); The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with monoallelic or biallelic variants have been reported (PMIDs: 34210994, 34441032); Variants in this gene are known to have variable expressivity (PMID: 34210994); This variant has been shown to be paternally inherited by trio analysis.
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.
Criteria applied: PS3,PS4
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-Hammarström 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.
ACMG classification criteria: PS3 supporting, PS4 strong, PP1 supporting
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.
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.
ACMG Criteria: PS3, PS4, PM1, PM3, PP5; Variant was found in heterozygous state
Immunoglobulin A deficiency 2 Pathogenic:3
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
See cases Pathogenic:1
ACMG classification criteria: PS3, PS4, PM3, BS2
Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at