LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_012452.3_c.310T_C_20261106_211755
Framework: ACMG/AMP 2015
Variant classification summary

NM_012452.3:c.310T>C

TNFRSF13B  · NP_036584.1:p.(Cys104Arg)  · NM_012452.3
GRCh37: chr17:16852187 A>G  ·  GRCh38: chr17:16948873 A>G
Gene: TNFRSF13B Transcript: NM_012452.3
Final call
Pathogenic
PS3 strong PS4 strong PM3 moderate PP1 supporting PP3 moderate BS4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TNFRSF13B
Transcript
NM_012452.3
Protein
NP_036584.1:p.(Cys104Arg)
gnomAD AF
0.0054409977289425395 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong is supported by concordant human-cell and murine assays showing impaired TACI function.
2
Pathogenic: PS4 strong is supported by autoimmunity in 8/15 carriers versus 1/11 non-carriers, OR 11.43 with a 95% CI excluding 1.0.
3
Pathogenic: PM3 moderate is supported by C104R in trans with the pathogenic S194X allele in an affected individual.
4
Pathogenic: PP1 supporting reflects multiple affected relatives carrying C104R, limited by reduced penetrance.
5
Pathogenic: PP3 moderate reflects REVEL 0.919 meeting the calibrated moderate threshold.
6
BS4 supporting documents inconsistent segregation but does not satisfy a benign rule on its own.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) are sufficient for a Pathogenic call; BS4 supporting does not satisfy a benign rule and therefore does not create conflicting evidence.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: reviewed records report Cys104Arg as c.310T>C, with no established pathogenic alternate nucleotide change producing the same amino-acid substitution.
clinvar PMID:16007087 PMID:22983507 PMID:23237420
PS2 Not assessed Not assessed: no documented proband trio testing confirms both maternity and paternity for this variant.
PS3 Met Met, strong: independent human-cell and murine assays consistently showed reduced ligand binding, signaling, B-cell responses, and antibody production for C104R/C76R.
PMID:16007087 PMID:17492055 PMID:20889194 PMID:21419480 PMID:21458042 PMID:23237420
PS4 Met 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.
PM1 Not assessed Not assessed: Cys104 lies in functional CRD2, but no complete evidence establishes absence of benign variation across that domain.
PMID:16007087 PMID:21419480 PMID:23237420 gnomad_v4
PM2 Not met Not met: non-cancer AF is 0.00335751 and gnomAD v4.1 filtering FAF is 0.0065711, both above the PM2 threshold of 0.0001.
gnomad_v2 gnomad_v4
PM3 Met Met: one affected individual with CVID was compound heterozygous for C104R/S194X, establishing C104R in trans with the S194X stop-codon allele.
PMID:23237420
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: no reviewed record documents a different pathogenic missense substitution at residue Cys104; reported comparators affect other residues.
PMID:16007087 PMID:21419480 PMID:23237420 PMID:22983507
PM6 Not assessed Not assessed: the available reports describe familial transmission, not an assumed de novo proband variant without parental confirmation.
PMID:22983507
PP1 Met Met at supporting: multiple affected relatives carried C104R, but seven-member familial data showed inconsistent phenotype correlation and reduced penetrance.
PMID:22983507
PP2 Not assessed Not assessed: missense disease involvement is documented, but the required gene-level low benign-missense rate is not established; gnomAD AF is 0.005441.
PMID:16007087 PMID:21419480 PMID:23237420 gnomad_v4
PP3 Met Met at moderate strength: REVEL 0.919 meets the >=0.773 PP3 threshold but remains below the >=0.932 strong threshold.
revel
PP4 Not met Not met: C104R occurs in affected and healthy relatives with variable penetrance, so the phenotype is not highly specific for a single genetic etiology.
PMID:22983507 PMID:23237420
PP5 Not met Not met: ClinVar has no exact-variant expert-panel classification, only laboratory submissions with conflicting aggregate labels.
clinvar
BA1 Not met Not met: the highest filtering FAF is 0.0065711, well below the BA1 stand-alone threshold of 0.05.
gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: filtering FAF is 0.0065711, but variable penetrance and missing prevalence inputs prevent a defensible maximum-credible-frequency comparison.
gnomad_v2 gnomad_v4 PMID:21458042 PMID:23237420
BS2 N/A Not applicable: C104R has variable penetrance, so homozygotes in gnomAD or one unaffected sibling cannot satisfy the full-penetrance early-age BS2 condition.
gnomad_v2 gnomad_v4 PMID:23237420
BS3 Not met Not met: every variant-specific functional study reviewed showed impaired TACI expression, ligand binding, signaling, B-cell function, or antibody responses rather than normal function.
PMID:16007087 PMID:17492055 PMID:20889194 PMID:21419480 PMID:21458042 PMID:23237420
BS4 Met Met at supporting: affected and unaffected relatives showed inconsistent C104R phenotype correlation, including an affected CVID child reported without the variant.
PMID:22983507
BP1 Not assessed Not assessed: TNFRSF13B disease literature includes missense and truncating variants, without evidence that disease is primarily truncation-driven.
PMID:16007087 PMID:23237420 PMID:21419480
BP2 Not met Not met: C104R was observed in trans with S194X, but no cis pathogenic-variant observation exists and the disorder is not a fully penetrant dominant condition.
PMID:23237420
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.919 exceeds the <=0.29 BP4 supporting threshold, while SpliceAI is excluded for this missense variant.
revel
BP5 Not assessed Not assessed: no case-specific alternate molecular basis is documented for a patient carrying this exact variant.
BP6 Not met Not met: no exact-variant expert-panel benign classification is present; the only Likely benign assertion is a laboratory submission.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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