ClinVar Genomic variation as it relates to human health
NM_012452.3(TNFRSF13B):c.236A>G (p.Tyr79Cys)
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.
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.
Likely pathogenic(4); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012452.3(TNFRSF13B):c.236A>G (p.Tyr79Cys)
Variation ID: 281110 Accession: VCV000281110.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p11.2 17: 16948947 (GRCh38) [ NCBI UCSC ] 17: 16852261 (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 Dec 6, 2016 Mar 16, 2024 Dec 2, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_012452.3:c.236A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036584.1:p.Tyr79Cys missense NC_000017.11:g.16948947T>C NC_000017.10:g.16852261T>C NG_007281.1:g.28142A>G LRG_120:g.28142A>G LRG_120t1:c.236A>G LRG_120p1:p.Tyr79Cys - Protein change
- Y79C
- Other names
- -
- Canonical SPDI
- NC_000017.11:16948946:T:C
-
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 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00018
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00023
1000 Genomes Project 30x 0.00031
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 |
329 | 434 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 4, 2022 | RCV000327211.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 12, 2022 | RCV000648139.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 12, 2023 | RCV000723608.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 2, 2023 | RCV003947825.1 |
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
(Apr 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605398.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
Uncertain significance
(Nov 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331382.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Uncertain significance
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Immunodeficiency, common variable, 2
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512526.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PM3 supporting, PP3
Geographic origin: Brazil
|
|
Uncertain significance
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516100.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(Oct 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Immunodeficiency, common variable, 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000769953.6
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the TNFRSF13B protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the TNFRSF13B protein (p.Tyr79Cys). This variant is present in population databases (rs72553876, gnomAD 0.05%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID), IgG subclass deficiency, and/or primary immune disorders (PMID: 18981294, 22884984, 32581362, 34093558). ClinVar contains an entry for this variant (Variation ID: 281110). 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. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 18954329, 21419480, 21458042). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001789899.5
First in ClinVar: Aug 21, 2021 Last updated: May 27, 2023 |
Comment:
Identified in the presence of a second TNFRSF13B variant in siblings with IgG subclass deficiency, one of whom had recurrent infections requiring IVIG therapy; however, … (more)
Identified in the presence of a second TNFRSF13B variant in siblings with IgG subclass deficiency, one of whom had recurrent infections requiring IVIG therapy; however, their heterozygous mother was unaffected and father with dysgammaglobulinemia or IgG subclass deficiency was not tested (Salzer et al., 2009); Identified heterozygous in a patient with a personal history suggestive of common variable immune deficiency in published literature, though clinical details and segregation information were not provided (Hou et al., 2020); Identified heterozygous in a patient with recurrent pneumonia, recurrent gastroenteritis, and chronic oral herpes lesions in published literature, though segregation information was not provided (Engelbrecht et al., 2021); Surface expression studies support that the Y79C variant is damaging to the TNFRSF13B protein (Fried et al., 2011); 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: 18954329, 21458042, 22884984, 18981294, 32581362, 21419480, 34093558, 31980526) (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: SCV002020243.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Dec 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
TNFRSF13B-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004759997.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TNFRSF13B c.236A>G variant is predicted to result in the amino acid substitution p.Tyr79Cys. This variant has been reported in the compound heterozygous state in … (more)
The TNFRSF13B c.236A>G variant is predicted to result in the amino acid substitution p.Tyr79Cys. This variant has been reported in the compound heterozygous state in two individuals with IgG subclass deficiency from the same family (Salzer et al. 2009. PubMed ID: 18981294). Of note, this variant was also seen in the heterozygous state in a healthy member of that same family (Salzer et al. 2009. PubMed ID: 18981294). Functional analysis showed that the c.236A>G variant leads to a reduction in protein activity as compared to wild-type (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical Utility of Whole Exome Sequencing and Targeted Panels for the Identification of Inborn Errors of Immunity in a Resource-Constrained Setting. | Engelbrecht C | Frontiers in immunology | 2021 | PMID: 34093558 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
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 C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice. | Bacchelli C | The Journal of allergy and clinical immunology | 2011 | PMID: 21458042 |
Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. | Fried AJ | The Journal of allergy and clinical immunology | 2011 | PMID: 21419480 |
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 |
Abstracts of the 13th Meeting of the European Society for Immunology. October 16-19, 2008. 's-Hertogenbosch, The Netherlands. | - | Clinical and experimental immunology | 2008 | PMID: 18954329 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TNFRSF13B | - | - | - | - |
Text-mined citations for rs72553876 ...
HelpRecord last updated Mar 17, 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.