rs34562254

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012452.3(TNFRSF13B):c.752C>T(p.Pro251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,610,656 control chromosomes in the GnomAD database, including 13,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1409 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11783 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.825

Publications

63 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:

ENSG00000307457 (HGNC:):

ENSG00000307457 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022192597).

BP6

Variant 17-16939677-G-A is Benign according to our data. Variant chr17-16939677-G-A is described in ClinVar as Benign. ClinVar VariationId is 322025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 link	c.752C>T	p.Pro251Leu	missense_variant	Exon 5 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.752C>T	p.Pro251Leu	missense_variant	Exon 5 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19408

AN:

152080

Hom.:

1411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.0987

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.139

AC:

34438

AN:

248042

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.406

Gnomad FIN exome

AF:

0.0991

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.115

AC:

168414

AN:

1458458

Hom.:

11783

Cov.:

AF XY:

0.117

AC XY:

85143

AN XY:

724934

show subpopulations

African (AFR)

AF:

0.135

AC:

4501

AN:

33430

American (AMR)

AF:

0.103

AC:

4565

AN:

44528

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3610

AN:

26014

East Asian (EAS)

AF:

0.382

AC:

15145

AN:

39618

South Asian (SAS)

AF:

0.160

AC:

13723

AN:

85928

European-Finnish (FIN)

AF:

0.0972

AC:

5184

AN:

53306

Middle Eastern (MID)

AF:

0.127

AC:

728

AN:

5752

European-Non Finnish (NFE)

AF:

0.102

AC:

113099

AN:

1109646

Other (OTH)

AF:

0.130

AC:

7859

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

8837

17674

26512

35349

44186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4310

8620

12930

17240

21550

<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:

0.128

AC:

19407

AN:

152198

Hom.:

1409

Cov.:

AF XY:

0.130

AC XY:

9708

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.134

AC:

5562

AN:

41526

American (AMR)

AF:

0.122

AC:

1860

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

487

AN:

3472

East Asian (EAS)

AF:

0.403

AC:

2075

AN:

5150

South Asian (SAS)

AF:

0.156

AC:

754

AN:

4822

European-Finnish (FIN)

AF:

0.0987

AC:

1047

AN:

10608

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7179

AN:

67998

Other (OTH)

AF:

0.111

AC:

235

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

874

1748

2623

3497

4371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.122

Hom.:

2741

Bravo

AF:

0.129

TwinsUK

AF:

0.104

AC:

384

ALSPAC

AF:

0.0981

AC:

378

ESP6500AA

AF:

0.134

AC:

589

ESP6500EA

AF:

0.110

AC:

945

ExAC

AF:

0.139

AC:

16847

Asia WGS

AF:

0.249

AC:

867

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 04, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28728263) -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

Immunodeficiency, common variable, 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

L;.

PhyloP100

0.82

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.26

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.73

P;P

Vest4

0.049

MPC

0.013

ClinPred

0.015

GERP RS

0.88

Varity_R

0.022

gMVP

0.074

Mutation Taster

=100/0

polymorphism (auto)

(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