17-16948968-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012452.3(TNFRSF13B):c.215G>A(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,006 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 13 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008713514).

BP6

Variant 17-16948968-C-T is Benign according to our data. Variant chr17-16948968-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 322027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-16948968-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00257 (391/152164) while in subpopulation NFE AF= 0.00462 (314/68012). AF 95% confidence interval is 0.0042. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 link	c.215G>A	p.Arg72His	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.215G>A	p.Arg72His	missense_variant	Exon 3 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.00257

AC:

391

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00202

AC:

507

AN:

251186

Hom.:

AF XY:

0.00185

AC XY:

251

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00345

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00368

AC:

5376

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

2519

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.000581

Gnomad4 NFE exome

AF:

0.00450

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00257

AC:

391

AN:

152164

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000699

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00462

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00352

Hom.:

Bravo

AF:

0.00251

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00172

AC:

209

EpiCase

AF:

0.00327

EpiControl

AF:

0.00320

ClinVar

Significance: Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF13B: PM5, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 24, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18981294, 17392797, 16007087, 17983875, 17464555, 22884984, 26122175, 17392798, 32581362) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Aug 04, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF13B c.215G>A (p.Arg72His) results in a non-conservative amino acid change located in the TACI, cysteine-rich domain (IPR015384) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 394334 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 exomes dataset, and v3 genomes dataset), including 2 homozygotes. The observed variant frequency is considerably higher than the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype, strongly suggesting that the variant is benign. The variant, c.215G>A, also has been reported in the literature (in heterozygous and compound heterozygous state) in individuals affected with Common Variable Immunodeficiency, but has also been observed in unaffected individuals and family members (e.g. Salzer_2005, Freiberger_2012, Pulvirenti_2016). These reports do not provide unequivocal conclusions about association of the variant with Common Variable Immunodeficiency. The variant was found at frequencies comparable in CVID patient cohorts and healthy controls in multiple case-control studies (e.g. Salzer_2009, van Schouwenburg_2015) and in a meta-analysis of cases and controls from the literature (Freiberger_2012). A publication reported experimental evidence and demonstrated decreased production of IgG and IgA after APRIL stimulation of B cells derived from a patient carrying the variant in heterozygous state. However, in this study B cells of subjects with CVID but no TNFRSF13B mutations were at least as dysfunctional as B cells of subjects with CVID, who had monoallelic- or biallelic TNFRSF13B mutations; therefore, this study doesn't allow convincing conclusions about the variant effect (Zhang_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Immunodeficiency, common variable, 2

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Common Variable Immune Deficiency, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2

Benign:1

Jul 15, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in several individuals with common variable immunodeficiency (CVID) as well as in at least 2 individuals with antibody deficiency (Salzer 2005 PMID:16007087, Pan-Hammarstrom 2007 PMID:17392797, Zhang 2007 PMID:179838875, Freiberger 2012 PMID:22884984, Turro 2020 PMID:32581362, Rojas-Restrepo 2021 PMID:34975878). Of note, multiple publications list this variant as a polymorphism. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.4% (314/68020) including 2 homozygotes (https://gnomad.broadinstitute.org/variant/17-16948968-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:322027). This variant amino acid Histidine (His) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.36

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.11

.;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.090

.;N;.

REVEL

Uncertain

0.50

Sift

Benign

0.31

.;T;.

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0030, 0.0020

.;B;B

Vest4

0.19

MVP

0.32

MPC

0.013

ClinPred

0.0068

GERP RS

-9.9

Varity_R

0.054

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over