rs34557412

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM5PP3_ModeratePP5_Strong

The NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00544 (AC=8,783) in the gnomAD database across 1,614,226 control chromosomes, including 32 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00662. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV000649856: Experimental studies have shown that this missense change affects TNFRSF13B function (PMID:16007087, 20889194, 21419480, 21458042, 23237420, 24051380)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C104Y: Pathogenic/Likely_pathogenic (ClinVar VariationId 645207, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Immunoglobulin a deficiency 2 (igad2) Immunodeficiency, common variable, 2 (cvid2); it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 28 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:47U:5B:1O:2

Conservation

PhyloP100: 4.18

Publications

157 publications found

Variant links:

Genes affected

TNFRSF13B (HGNC:18153): (TNF receptor superfamily member 13B) 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]

TNFRSF13B Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

TNFRSF13B links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_012452.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000649856: Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 16007087, 20889194, 21419480, 21458042, 23237420, 24051380).; SCV002058245: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20889194, 21419480).; SCV005685537: "In vitro functional studies and murine models demonstrate that the variant results in impaired downstream signaling (Bacchelli C et al., PMID: 21458042; Lee JJ et al., PMID: 20889194; Martinez-Gallo M et al., PMID: 23237420; Salzer U et al., PMID: 18981294)."; SCV000329550: Published functional studies demonstrate C104R results in reduced surface expression and elimination of ligand binding, supporting a damaging effect (Lee et al., 2010; Fried et al., 2011); SCV000605391: Additionally, functional studies show that this variant disrupts protein signaling (Martinez-Gallo 2013, Salzer 2005).; SCV002070496: Functional studies have demonstrated that this sequence change affects ligand binding and reduces protein expression (PMID: 16007087, 21419480, 23237420).; SCV000699342: Multiple experimental studies suggest the variant causes significant defects to protein function. Specifically, protein expression and ligand binding were demonstrated to be significantly diminished (Bacchelli_2011, Salzer_2005).; SCV002495994: Numerous functional studies including mouse models have demonstrated the impact of this variant by reducing expression on the surface of B-cells, impairing bindings with BAFF and APRIL and defective antibody production (Salzer 2005 PMID:16007087, Lee 2010 PMID:20889194, Fried 2011 PMID:21419480, Martinez-Galllo 2013 PMID:23237420).; SCV004046269: "In-vitro studies showed that this variant disrupts NF-κB/NF-AT signaling and leads to defective B-cell proliferation in response to stimulation." PMID:21419480, 23237420, 19605846; SCV004104594: Functional studies have shown the p.Cys104Arg variant impairs TACI ligand binding and B-cell function (Romberg et al. 2015. PubMed ID: 26100089; Lee et al. 2010. PubMed ID: 20889194).

PM5

Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C104Y: Pathogenic/Likely_pathogenic (ClinVar VariationId 645207, 2 stars)

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

PP5

ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (34/35 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_012452.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	NM_012452.3	MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	NP_036584.1	O14836-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	ENSP00000261652.2	O14836-1
TNFRSF13B	ENST00000583789.1	TSL:1	c.172T>C	p.Cys58Arg	missense	Exon 2 of 4	ENSP00000462952.1	O14836-2
TNFRSF13B	ENST00000579315.5	TSL:3	c.310T>C	p.Cys104Arg	missense	Exon 3 of 4	ENSP00000464069.1	J3QR67

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

597

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00579

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00350

AC:

879

AN:

251490

AF XY:

0.00343

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00425

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00544

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00560

AC:

8186

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

3875

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33480

American (AMR)

AF:

0.00416

AC:

186

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00283

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00675

AC:

7506

AN:

1112010

Other (OTH)

AF:

0.00477

AC:

288

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

535

1070

1605

2140

2675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152334

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41584

American (AMR)

AF:

0.00713

AC:

109

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00579

AC:

394

AN:

68018

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00422

EpiCase

AF:

0.00627

EpiControl

AF:

0.00605

Local populations

Turkish Variome

AF:

0.00312

AC:

AN:

6724

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00897

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; risk factor

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 2 (25)

not provided (17)

Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 (3)

TNFRSF13B-related disorder (2)

Common variable immunodeficiency (1)

Immune deficiency, familial variable (1)

Immunodeficiency, common variable, 1 (1)

Immunoglobulin A deficiency 2 (1)

Inborn genetic diseases (1)

not specified (1)

Severe SARS-CoV-2 infection, susceptibility to (1)

Immunodeficiency, common variable, 1;C3150354:Immunodeficiency, common variable, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.23

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.9

PhyloP100

4.2

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-9.1

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Varity_R

0.96

gMVP

0.67

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over