rs72553876

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3PP5BS1_Supporting

The NM_012452.3(TNFRSF13B):c.236A>G(p.Tyr79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 3.58

Publications

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

TNFRSF13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

PP5

Variant 17-16948947-T-C is Pathogenic according to our data. Variant chr17-16948947-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281110.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000197 (30/152298) while in subpopulation AMR AF = 0.00085 (13/15288). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 link	c.236A>G	p.Tyr79Cys	missense_variant	Exon 3 of 5	ENST00000261652.7	NP_036584.1	O14836-1Q4ACX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7 link	c.236A>G	p.Tyr79Cys	missense_variant	Exon 3 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000175

AC:

AN:

251394

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000278

AC:

406

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

195

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000322

AC:

358

AN:

1112012

Other (OTH)

AF:

0.000364

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000197

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41576

American (AMR)

AF:

0.000850

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000249

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Jun 26, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (PMID: 18981294); Identified in the heterozygous state in patients with features of TNFRSF13B-related immunodeficiency, though segregation information was not provided (PMID: 31980526, 34093558); Surface expression studies support that the Y79C variant is damaging to the TNFRSF13B protein (PMID: 21419480); 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, 32581362, 21419480, Pundit2023[abstract], 18981294, 34093558, 31980526) -

Immunodeficiency, common variable, 2

Pathogenic:1Uncertain:2

Oct 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 01, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PM3 supporting, PP3 -

Aug 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Pathogenic:1Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 07, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TNFRSF13B-related disorder

Pathogenic:1

Dec 02, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Pathogenic

0.81

D;D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.85

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

.;M;.

PhyloP100

3.6

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.9

.;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.83

MVP

0.89

MPC

0.084

ClinPred

0.48

GERP RS

5.0

Varity_R

0.82

gMVP

0.66

Mutation Taster

=7/93

disease causing (ClinVar)

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over