The TNFRSF13B NM_012452.3:c.310T>C (NP_036584.1:p.(Cys104Arg)) missense variant has previously been reported in somatic cancers (COSMIC; COSV55430181, n = 2 times). Experimental evidence: Independent human-cell and murine assays consistently showed reduced ligand binding, signaling, B-cell responses, and antibody production for C104R/C76R. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.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]
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: independent human-cell and murine assays consistently showed reduced ligand binding, signaling, B-cell responses, and antibody production for C104R/C76R.
Met: autoimmunity was 8/15 versus 1/11 in non-carriers, giving OR 11.43 (95% CI 1.15-113.12), above 5.0 with the interval excluding 1.0.
Met: one affected individual with CVID was compound heterozygous for C104R/S194X, establishing C104R in trans with the S194X stop-codon allele.
Met at supporting: multiple affected relatives carried C104R, but seven-member familial data showed inconsistent phenotype correlation and reduced penetrance.
Met at moderate strength: REVEL 0.919 meets the >=0.773 PP3 threshold but remains below the >=0.932 strong threshold.
Met at supporting: affected and unaffected relatives showed inconsistent C104R phenotype correlation, including an affected CVID child reported without the variant.
Pathogenic: PS3 strong and PS4 strong satisfy the generic ACMG/AMP rule for two strong pathogenic criteria, with additional PM3, PP1, and PP3 support.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 8,783 / 1,614,226 alleles. Recorded AF 0.005441. Recorded homozygote count 32.
This variant is present in gnomAD v2.1 (AF= 0.00347485; MAF= 0.34748%, 983/282890 alleles, homozygotes = 4) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00539515; MAF= 0.53952%, 697/129190 alleles, homozygotes = 3); grpmax FAF= 0.00508582.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.919. Refer to the recorded PP3/BP4 rationale for interpretation.
23 Pathogenic · 21 Likely pathogenic · 5 Uncertain significance · 1 Likely benign · 1 risk factor. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV55430181, n = 2 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 6 met · 10 not met · 7 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The queried variant is TNFRSF13B NP_036584.1:p.(Cys104Arg) (C104R), a missense change in the second extracellular cysteine-rich domain.
PS1 and PM5 are not met because the reviewed evidence does not provide a distinct pathogenic nucleotide change producing the same amino acid or a distinct pathogenic missense substitution at residue 104.
PM1, PP2, and BP1 remain not assessed because the supplied evidence does not establish their required domain-wide or gene-level premises.
The segregation evidence supports PP1 and BS4 only at supporting strength because C104R occurs in multiple affected relatives but also in unaffected relatives and shows inconsistent phenotype correlation.
PS2 and PM6 are not assessed because no proband-specific de novo or assumed-de novo observation with parental testing information is documented.
PS3 is met at strong strength because multiple independent, variant-specific human-cell and murine functional studies with control comparisons consistently demonstrate impaired TACI function.
BS3 is not met because no reviewed study demonstrates normal C104R protein function or splicing; the available studies instead show damaging effects.
PS4 is met from the verified exact-variant familial phenotype comparison, with OR 11.43 and 95% CI 1.15-113.12 satisfying the stated >5.0 and confidence-interval criteria.
PP4 is not met because C104R has incomplete penetrance and variable clinical expression rather than a highly specific phenotype for a single genetic etiology.
PP5 and BP6 are not met because ClinVar has no exact-variant expert-panel classification; BP5 is not assessed because no alternate molecular basis is documented for the interpreted case.
The variant is missense (NM_012452.3:c.310T>C; p.(Cys104Arg)); generic PP3/BP4 therefore use REVEL only.
REVEL 0.919 meets PP3 moderate but not PP3 strong, and does not meet any BP4 threshold.
SpliceAI and uncalibrated BayesDel are excluded from these criterion decisions.
No criteria match.
Multiple independent, variant-specific functional studies support a damaging effect for TNFRSF13B c.310T>C (p.Cys104Arg/C104R). Human-cell assays demonstrated markedly reduced TACI surface expression, impaired BAFF/APRIL ligand binding, near-absent NF-kB or NF-AT signaling, and impaired downstream B-cell responses. Independent studies also showed absent or reduced APRIL-induced proliferation, class-switching, immunoglobulin production, and AID expression. Physiologically relevant murine models of the equivalent C76R substitution reproduced impaired antibody responses, B-cell proliferation, immunoglobulin secretion, and B-cell homeostasis. The evidence is concordant across biochemical, cellular, ex vivo, and in vivo assays and includes wild-type/control comparisons, supporting PS3 at strong strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. ... Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
The verified abstract for PMID:22697072 reports the exact C104R variant in 8 of 15 heterozygous relatives with autoimmunity versus 1 of 11 non-carrier relatives. Treating these groups as affected-phenotype and control groups gives OR=(8x10)/(7x1)=11.43 and a Woolf 95% CI of 1.15-113.12. The governing PS4 comparison is OR >5.0 with a confidence interval that does not include 1.0: 11.43 > 5.0 and 1.15-113.12 excludes 1.0, so PS4 is met. The study is familial and evaluates autoimmunity rather than a narrowly defined single disease, so human review is retained.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 is met for NM_012452.3:c.310T>C (p.Cys104Arg). In the seven-family study, an affected individual with CVID carried C104R/S194X, explicitly described as compound heterozygous, with C104R and S194X carried separately in the family; this establishes the queried variant in trans with the S194X stop-codon allele. The same study also reports three C104R homozygotes, but those observations are not needed for PM3. The evidence directly satisfies the generic recessive PM3 definition and includes familial phase information. No quantitative generic strength threshold was supplied, so no strength tier is assigned.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The exact C104R variant is reported in familial studies with multiple affected relatives. PMID:22983507 describes a seven-member family carrying the variant, including an index patient with CVID and SLE, while the paper reports that the variant did not correlate consistently with clinical phenotype. The literature bundle also reports the exact variant in two of three index children with CVID and in relatives with selective IgA deficiency or recurrent infections. This supports cosegregation with disease in multiple affected family members, but reduced penetrance and marked intrafamilial variability limit the evidence to supporting strength.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The variant is a missense substitution, p.(Cys104Arg), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.919, meeting the supplied PP3 moderate threshold of >=0.773 but not the strong threshold of >=0.932. The threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only.
Non-segregation is documented in familial C104R reports. PMID:22983507 describes affected and unaffected members within the same family and states that C104R did not correlate consistently with clinical phenotype; the literature bundle additionally reports a CVID index child who lacked the variant despite other affected relatives carrying it. This supports lack of segregation in affected family members, but the finding is confounded by incomplete penetrance, variable clinical expression, and the possibility of phenocopy or additional genetic contributors.
Lack of segregation in affected members of a family.
The variant is NP_036584.1:p.(Cys104Arg) (C104R), and the reviewed reports describe this same c.310T>C/C104R change. No previously established pathogenic variant producing Cys104Arg through a different nucleotide substitution was identified in the available ClinVar and literature records; therefore the PS1 same-amino-acid criterion is not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM2 is not met because C104R is substantially more frequent than the generic supporting threshold in both all-comers and non-cancer population data. The lowest relevant total allele frequency is 0.00335751 in gnomAD v2.1 non-cancer data, and the highest filtering FAF is 0.0065711 in gnomAD v4.1; all exceed 0.0001. Homozygotes are also observed (4 in gnomAD v2.1 and 32 in gnomAD v4.1), so the variant is neither absent nor at an extremely low frequency compatible with the supplied PM2 threshold.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The queried variant changes Cys104 to Arg. The reviewed TNFRSF13B reports describe C104R and other missense variants at different residues, including Y79C, but do not document a different pathogenic missense substitution at residue 104. The required same-residue pathogenic comparator is therefore absent from the reviewed evidence.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available phenotype evidence is not highly specific for a disease with a single genetic etiology. C104R is reported in CVID-affected individuals, clinically healthy heterozygotes, and individuals with variable or incomplete phenotypes; TNFRSF13B-related antibody deficiency is also genetically heterogeneous. Therefore the PP4 specificity requirement is not met.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
ClinVar contains Pathogenic and Likely pathogenic laboratory submissions for the exact variant, but the record reports zero expert-panel submissions and conflicting classifications. Under the specified generic rule, ordinary laboratory submissions and aggregate ClinVar labels do not trigger PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The applicable filtering allele-frequency values are far below the stand-alone threshold: gnomAD v4.1 grpmax FAF=0.0065711 and gnomAD v2.1 grpmax FAF=0.00508582; the non-cancer subsets are also below threshold (v2.1 exomes grpmax FAF=0.00494465; v3.1 non-cancer genomes grpmax FAF=0.00604868). These are filtering FAF values rather than popmax point estimates, and the relevant observed-allele counts exceed 2000 for the grpmax populations. The maximum observed filtering FAF is 0.0065711, below 0.05.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
The reviewed variant-specific functional evidence does not show a lack of damaging effect. Instead, independent human-cell, patient-cell, ex vivo, and murine studies consistently demonstrate loss or reduction of TACI expression, ligand binding, signaling, B-cell proliferation, class switching, immunoglobulin production, or antibody responses. No well-established assay showing normal protein function or splicing for C104R was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP2 is not met. The available study documents C104R in trans with S194X in an affected individual, but the governing BP2 trans path requires a pathogenic variant in a fully penetrant dominant gene/disorder; TNFRSF13B-related antibody deficiency is reported with variable penetrance and both recessive and dominant-risk patterns, so that trans observation does not qualify. No observation of C104R in cis with another pathogenic variant was identified. The compound-heterozygous observation therefore supports PM3, not BP2.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The variant is a missense substitution, p.(Cys104Arg), so the governing generic rule selects the REVEL path only; the SpliceAI max delta of 0.011 cannot be used for BP4. REVEL is 0.919, which exceeds the supplied BP4 supporting threshold of <=0.29, so BP4 is not met. BayesDel is not usable because no generic ACMG-strength calibration is established.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only.
ClinVar has one Likely benign laboratory submission for the exact variant, but no expert-panel submission and conflicting classifications overall. Under the specified generic rule, this does not qualify for BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific evidence documents that NM_012452.3:c.310T>C arose de novo in the proband. The available evidence does not establish both maternity and paternity, does not document a negative family history, and does not provide a trio or parental testing result. Therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Cys104 is described as a conserved extracellular cysteine forming a disulfide bond with Cys93 and maintaining the second cysteine-rich domain; functional studies show impaired ligand binding and signaling. However, no VCEP domain table applies, and the available evidence does not establish that the complete relevant domain lacks benign variation, which is required for generic PM1.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
No case-specific evidence establishes that the variant was assumed to be de novo in the proband. The literature instead describes inherited familial transmission and unaffected carriers, and no proband parental testing or de novo observation is documented. Therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The evidence shows that TNFRSF13B has disease-associated missense variants, including C104R, and that C104R is relatively common in population data (gnomAD v4.1 AF 0.005441 with 32 homozygotes). It does not establish the required gene-level low rate of benign missense variation, so PP2 cannot be adjudicated from the supplied evidence.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
BS1 is not assessed rather than applied from the generic 1% default. The highest filtering FAF is 0.0065711, below 1%, but C104R is a known TNFRSF13B risk-associated allele observed in healthy heterozygotes and in a disorder with incomplete and variable penetrance. A publication reports C104R in approximately 0.5%-1% of reportedly healthy subjects, and another study reports clinically healthy carriers and an unaffected homozygous sibling. A maximum-credible-frequency calculation cannot be completed because disease prevalence, penetrance, allelic heterogeneity, and the fraction of disease attributable to this allele are not quantitatively specified in the case evidence. Therefore the frequency does not establish BS1, and the default alone is insufficient.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The supplied literature documents both missense and truncating TNFRSF13B variants and supports disease relevance for missense variation, including C104R. It does not establish that disease in this gene is caused primarily by truncating variants, so the BP1 gene-level premise cannot be confirmed.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
No case-specific evidence establishes that this exact variant was found in a patient with an alternate molecular basis for disease. The available literature describes variable TNFRSF13B phenotypes and functional findings but does not document the required alternate molecular diagnosis for the interpreted case.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_012452.3:c.310T>C in TNFRSF13B is a missense substitution predicted to produce NP_036584.1:p.(Cys104Arg). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for TNFRSF13B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_012452.3:c.310T>C in TNFRSF13B is a missense substitution predicted to produce NP_036584.1:p.(Cys104Arg). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for TNFRSF13B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BS2 is not applicable under its stated generic condition because the TNFRSF13B C104R phenotype is variably penetrant and clinically heterogeneous rather than a disorder for which full penetrance at an early age is established. gnomAD reports homozygotes (v2.1: 4; v4.1: 32), and PMID:23237420 describes an apparently unaffected homozygous sibling, but these observations cannot satisfy a full-penetrance early-age healthy-adult criterion for this disorder.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_012452.3:c.310T>C in TNFRSF13B is a missense substitution predicted to produce NP_036584.1:p.(Cys104Arg). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for TNFRSF13B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_012452.3:c.310T>C in TNFRSF13B is a missense substitution predicted to produce NP_036584.1:p.(Cys104Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TNFRSF13B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in TNFRSF13B, mapped onto the exon structure of NM_012452.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)7900 / 1,180,028 | 0.006729 hom |
| Admixed American295 / 60,022 | 0.00492 hom |
| Remaining individuals301 / 62,512 | 0.00481 hom |
| Ashkenazi Jewish80 / 29,606 | 0.0027 |
| Middle Eastern13 / 6,062 | 0.0021 |
| African/African American96 / 75,064 | 0.0013 |
| European (Finnish)72 / 64,048 | 0.0011 |
| South Asian26 / 91,086 | 0.00029 |
| European (non-Finnish)697 / 129,190 | 0.00543 hom |
| Remaining individuals31 / 7,228 | 0.0043 |
| Admixed American151 / 35,440 | 0.00431 hom |
| Ashkenazi Jewish25 / 10,370 | 0.0024 |
| African/African American42 / 24,970 | 0.0017 |
| European (Finnish)29 / 25,122 | 0.0012 |
| South Asian8 / 30,616 | 0.00026 |
This variant is present in gnomAD v4.1 (AF= 0.005441; MAF= 0.54410%, 8783/1614226 alleles, homozygotes = 32) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00669476; MAF= 0.66948%, 7900/1180028 alleles, homozygotes = 29); grpmax FAF= 0.0065711.
This variant is present in gnomAD v2.1 (AF= 0.00347485; MAF= 0.34748%, 983/282890 alleles, homozygotes = 4) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00539515; MAF= 0.53952%, 697/129190 alleles, homozygotes = 3); grpmax FAF= 0.00508582.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, p.(Cys104Arg), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.919, meeting the supplied PP3 moderate threshold of >=0.773 but not the strong threshold of >=0.932. The threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only.
The variant is a missense substitution, p.(Cys104Arg), so the governing generic rule selects the REVEL path only; the SpliceAI max delta of 0.011 cannot be used for BP4. REVEL is 0.919, which exceeds the supplied BP4 supporting threshold of <=0.29, so BP4 is not met. BayesDel is not usable because no generic ACMG-strength calibration is established.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_012452.3:c.310T>C in TNFRSF13B is a missense substitution predicted to produce NP_036584.1:p.(Cys104Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TNFRSF13B, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.919. BayesDel score = 0.52845.
10 paper records listed. 7 cited in the classification.
The mutation in family B affects a conserved cysteine residue (C104R) in the extracellular domain of TACI. Cys104 forms a disulfide bond with Cys93 and participates in the maintenance of the second cysteine-rich domain of TACI21.
Location Results: family B characterization; Figure 1a-b; Table 1; Figure 2a; Figure 3a-c
Context Study of 162 unrelated individuals with CVID, including multiplex families and sporadic cases, with EBV-transformed B-cell expression and ligand-binding assays, B-cell proliferation assays, and PBMC class-switch and IgG assays.
B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACI) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACI ligand.
Location Abstract and in vitro transfection assay results
Context Patient B cells and in vitro transfection assays evaluating human C104R and murine C76R TACI signaling with wild-type TACI comparison.
The murine TACI mutant C76R is the equivalent of the human TACI mutant C104R.
Location Abstract; Results sections on TNP-Ficoll responses and APRIL-induced proliferation and immunoglobulin production; Discussion
Context Murine transgenic TACI C76R expression on a TACI-heterozygous background; in vivo immunization and ex vivo APRIL-induced B-cell assays.
The most common TACI variants in CVID are C104R, in the ligand binding cysteine-rich domain 2 (CRD2), and A181E, in the transmembrane (TM) domain of TACI. ... Surface expression of the CRD2 mutants Y79C and C104R was modestly decreased to ~ half of WT, while that of the L171R mutant was reduced ~8 fold.
Location Results, paragraphs describing Figure 1B-C and Figure 2A-C; discussion of the C76R murine equivalent
Context 293T transfectant assays of surface expression, BAFF binding, APRIL-induced NF-kB and NF-AT reporter activity, and co-transfection testing for dominant-negative effects.
A knock-in mouse with the equivalent mutation murine TACI (mTACI) C76R was generated as a physiologically relevant model of human disease.
Location Abstract, Background and Methods; Results sections on NF-kB activation and C76R knock-in mice
Context Human TACI expression, ligand-binding, and NF-kB assays plus C57BL/6 knock-in mice with murine C76R studied in heterozygous and homozygous states.
A 310T→C nucleotide substitution in the TNFRSF13B gene leads to C104R (cysteine 104→arginine) mutation in the transmembrane activator and calcium-modulator cyclophilin and ligand interactor (TACI) protein [5].
Location Introduction, paragraph describing the TNFRSF13B nucleotide substitution and C104R; Results, Molecular Studies and Flow Cytometry Analysis; Discussion
Context Family segregation study of seven related individuals with exon 3 sequencing, flow-cytometric TACI expression, immunoglobulin measurements, vaccine-response testing, and lymphocyte proliferation assays.
The extracellular mutation (C104R) leads to a disruption of the second CRD, impairing BAFF and APRIL binding.
Location Introduction, p. 469; Table I, Families D, E, and F; Results, 'Heterozygous and homozygous mutations impair APRIL binding'
Context Seven-family study of CVID patients, mutation-bearing relatives, and healthy controls using EBV-transformed B-cell lines and peripheral blood B cells, ligand-binding assays, TLR9 activation, AID mRNA quantification, and APRIL-induced immunoglobulin production assays.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.005441; MAF= 0.54410%, 8783/1614226 alleles, homozygotes = 32) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00669476; MAF= 0.66948%, 7900/1180028 alleles, homozygotes = 29); grpmax FAF= 0.0065711.
This variant is present in gnomAD v2.1 (AF= 0.00347485; MAF= 0.34748%, 983/282890 alleles, homozygotes = 4) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00539515; MAF= 0.53952%, 697/129190 alleles, homozygotes = 3); grpmax FAF= 0.00508582.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (23 clinical laboratories) and as Likely pathogenic (21 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratory) and as risk factor (1 clinical laboratory). (ClinVarID = 5302)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.919. BayesDel score = 0.52845.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55430181, n = 2 times).
This variant does not lie in a statistically significant hotspot.