The TNFRSF13B c.311G>A variant is predicted to result in the amino acid substitution p.Cys104Tyr. This variant has been reported in the compound heterozygous and heterozygous state in numerous patients with common variable immunodeficiency disorders (CVIDs) (Salzer et al. 2009. PubMed ID: 18981294; Pulvirenti et al. 2016. PubMed ID: 27123465; Freiberger et al. 2012. PubMed ID: 22884984; Baxter et al. 2021. PubMed ID: 33864888; Grossi et al. 2021. PubMed ID: 34573280). This variant was also shown to segregate in the compound heterozygous in two siblings with CVIDs and the carrier parents were unaffected (Salzer et al. 2009. PubMed ID: 18981294). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-16852186-C-T). In ClinVar, this variant has been interpreted as pathogenic and likely pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/645207/). A different substitution affecting the same amino acid (p.Cys104Arg) has also been reported in association with CVIDs (Salzer et al. 2005. PubMed ID: 16007087; Freiberger et al. 2012. PubMed ID: 22884984; Barroeta Seijas et al. 2012. PubMed ID: 22697072; Martinez-Gallo et al. 2012. PubMed ID: 23237420). Based on this evidence, we interpret the c.311G>A (p.Cys104Tyr) variant as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_012452.3(TNFRSF13B):c.311G>A (p.Cys104Tyr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012452.3(TNFRSF13B):c.311G>A (p.Cys104Tyr)
Variation ID: 645207 Accession: VCV000645207.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p11.2 17: 16948872 (GRCh38) [ NCBI UCSC ] 17: 16852186 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 14, 2019 Sep 29, 2024 Jan 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_012452.3:c.311G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036584.1:p.Cys104Tyr missense NC_000017.11:g.16948872C>T NC_000017.10:g.16852186C>T NG_007281.1:g.28217G>A LRG_120:g.28217G>A LRG_120t1:c.311G>A LRG_120p1:p.Cys104Tyr - Protein change
- C104Y
- Other names
- -
- Canonical SPDI
- NC_000017.11:16948871:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00011
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00016
The Genome Aggregation Database (gnomAD) 0.00016
1000 Genomes Project 0.00020
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TNFRSF13B | - | - |
GRCh38 GRCh37 |
339 | 444 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000799248.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2022 | RCV002283512.1 | |
|
TNFRSF13B-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 10, 2023 | RCV003396393.4 |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV003130049.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Immunodeficiency, common variable, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002759352.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Clinical Features:
Hydrocele testis (present) , Cholelithiasis (present) , Ventricular septal defect (present) , Mitral valve prolapse (present) , Left ventricular hypertrophy (present) , Thrombocytopenia (present) , … (more)
Hydrocele testis (present) , Cholelithiasis (present) , Ventricular septal defect (present) , Mitral valve prolapse (present) , Left ventricular hypertrophy (present) , Thrombocytopenia (present) , Neutropenia (present) , Pancytopenia (present) , Lymphopenia (present) , Normochromic anemia (present) , Normocytic anemia (present) , Anemia (present) , Hyperbilirubinemia (present) , Abnormal circulating IgM concentration (present) (less)
|
|
|
Likely pathogenic
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
TNFRSF13B-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104101.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TNFRSF13B c.311G>A variant is predicted to result in the amino acid substitution p.Cys104Tyr. This variant has been reported in the compound heterozygous and heterozygous … (more)
The TNFRSF13B c.311G>A variant is predicted to result in the amino acid substitution p.Cys104Tyr. This variant has been reported in the compound heterozygous and heterozygous state in numerous patients with common variable immunodeficiency disorders (CVIDs) (Salzer et al. 2009. PubMed ID: 18981294; Pulvirenti et al. 2016. PubMed ID: 27123465; Freiberger et al. 2012. PubMed ID: 22884984; Baxter et al. 2021. PubMed ID: 33864888; Grossi et al. 2021. PubMed ID: 34573280). This variant was also shown to segregate in the compound heterozygous in two siblings with CVIDs and the carrier parents were unaffected (Salzer et al. 2009. PubMed ID: 18981294). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-16852186-C-T). In ClinVar, this variant has been interpreted as pathogenic and likely pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/645207/). A different substitution affecting the same amino acid (p.Cys104Arg) has also been reported in association with CVIDs (Salzer et al. 2005. PubMed ID: 16007087; Freiberger et al. 2012. PubMed ID: 22884984; Barroeta Seijas et al. 2012. PubMed ID: 22697072; Martinez-Gallo et al. 2012. PubMed ID: 23237420). Based on this evidence, we interpret the c.311G>A (p.Cys104Tyr) variant as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Jun 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003809577.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Immunodeficiency, common variable, 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000938902.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 104 of the TNFRSF13B protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 104 of the TNFRSF13B protein (p.Cys104Tyr). This variant is present in population databases (rs72553879, gnomAD 0.02%). This missense change has been observed in individual(s) with CVID and IgA deficiency and common variable immunodeficiency (CVID) (PMID: 18981294, 22884984, 27123465). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 645207). 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 TNFRSF13B protein function with a positive predictive value of 80%. This variant disrupts the p.Cys104 amino acid residue in TNFRSF13B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16007087, 19779048, 22697072, 22884984, 22983507, 23237420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325054.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Identified in the single heterozygous state in several individuals with immune disorders and primary antibody deficiencies, however, some individuals harbored additional variants in other genes … (more)
Identified in the single heterozygous state in several individuals with immune disorders and primary antibody deficiencies, however, some individuals harbored additional variants in other genes associated with immunodeficiency (PMID: 34573280, 27123465, 32581362, 33864888); 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: 22884984, 27123465, 37007115, 33864888, 32581362, 18981294, 38054159, 34573280) (less)
|
|
|
Pathogenic
(May 01, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Immunodeficiency, common variable, 1
Affected status: yes
Allele origin:
germline
|
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573412.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Immunodeficiency, common variable, 2
Affected status: unknown
Allele origin:
germline
|
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573405.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
|
Comment:
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 104 of the TNFRSF13B protein (p.Cys104Tyr). This variant is present in population databases (rs72553879, gnomAD 0.02%). This missense change has been observed in individual(s) with CVID and IgA deficiency and common variable immunodeficiency (CVID) (PMID: 18981294, 22884984, 27123465). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 645207). 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 TNFRSF13B protein function with a positive predictive value of 80%. This variant disrupts the p.Cys104 amino acid residue in TNFRSF13B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16007087, 19779048, 22697072, 22884984, 22983507, 23237420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Identified in the single heterozygous state in several individuals with immune disorders and primary antibody deficiencies, however, some individuals harbored additional variants in other genes associated with immunodeficiency (PMID: 34573280, 27123465, 32581362, 33864888); 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: 22884984, 27123465, 37007115, 33864888, 32581362, 18981294, 38054159, 34573280)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The TNFRSF13B c.311G>A variant is predicted to result in the amino acid substitution p.Cys104Tyr. This variant has been reported in the compound heterozygous and heterozygous state in numerous patients with common variable immunodeficiency disorders (CVIDs) (Salzer et al. 2009. PubMed ID: 18981294; Pulvirenti et al. 2016. PubMed ID: 27123465; Freiberger et al. 2012. PubMed ID: 22884984; Baxter et al. 2021. PubMed ID: 33864888; Grossi et al. 2021. PubMed ID: 34573280). This variant was also shown to segregate in the compound heterozygous in two siblings with CVIDs and the carrier parents were unaffected (Salzer et al. 2009. PubMed ID: 18981294). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-16852186-C-T). In ClinVar, this variant has been interpreted as pathogenic and likely pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/645207/). A different substitution affecting the same amino acid (p.Cys104Arg) has also been reported in association with CVIDs (Salzer et al. 2005. PubMed ID: 16007087; Freiberger et al. 2012. PubMed ID: 22884984; Barroeta Seijas et al. 2012. PubMed ID: 22697072; Martinez-Gallo et al. 2012. PubMed ID: 23237420). Based on this evidence, we interpret the c.311G>A (p.Cys104Tyr) variant as likely pathogenic.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 104 of the TNFRSF13B protein (p.Cys104Tyr). This variant is present in population databases (rs72553879, gnomAD 0.02%). This missense change has been observed in individual(s) with CVID and IgA deficiency and common variable immunodeficiency (CVID) (PMID: 18981294, 22884984, 27123465). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 645207). 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 TNFRSF13B protein function with a positive predictive value of 80%. This variant disrupts the p.Cys104 amino acid residue in TNFRSF13B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16007087, 19779048, 22697072, 22884984, 22983507, 23237420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Identified in the single heterozygous state in several individuals with immune disorders and primary antibody deficiencies, however, some individuals harbored additional variants in other genes associated with immunodeficiency (PMID: 34573280, 27123465, 32581362, 33864888); 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: 22884984, 27123465, 37007115, 33864888, 32581362, 18981294, 38054159, 34573280)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes. | Pulvirenti F | Journal of immunology research | 2016 | PMID: 27123465 |
| TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. | Martinez-Gallo M | The Journal of allergy and clinical immunology | 2013 | PMID: 23237420 |
| Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). | Koopmans W | Journal of clinical immunology | 2013 | PMID: 22983507 |
| Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. | Freiberger T | Human immunology | 2012 | PMID: 22884984 |
| The impact of TACI mutations: from hypogammaglobulinemia in infancy to autoimmunity in adulthood. | Barroeta Seijas AB | International journal of immunopathology and pharmacology | 2012 | PMID: 22697072 |
| Role of TNFRSF13B variants in patients with common variable immunodeficiency. | Martínez-Pomar N | Blood | 2009 | PMID: 19779048 |
| Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. | Salzer U | Blood | 2009 | PMID: 18981294 |
| Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. | Salzer U | Nature genetics | 2005 | PMID: 16007087 |
Text-mined citations for rs72553879 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.