rs74811083

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.563A>T(p.Lys188Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,611,408 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K188T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 52 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 60 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.140

Publications

8 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=0.0057032406).

BP6

Variant 17-16940394-T-A is Benign according to our data. Variant chr17-16940394-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 link	c.563A>T	p.Lys188Met	missense_variant	Exon 4 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.563A>T	p.Lys188Met	missense_variant	Exon 4 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2206

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000646

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00346

AC:

868

AN:

250762

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.0496

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00144

AC:

2107

AN:

1459396

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

891

AN XY:

725466

show subpopulations

African (AFR)

AF:

0.0542

AC:

1813

AN:

33476

American (AMR)

AF:

0.00177

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000714

AC:

AN:

84006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00158

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1112000

Other (OTH)

AF:

0.00260

AC:

157

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

138

277

415

554

692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0145

AC:

2207

AN:

152012

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1017

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0507

AC:

2103

AN:

41518

American (AMR)

AF:

0.00431

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000646

AC:

AN:

4644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67994

Other (OTH)

AF:

0.00997

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00111

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0493

AC:

217

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00463

AC:

560

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 17, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

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 22, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TNFRSF13B c.563A>T (p.Lys188Met) results in a non-conservative amino acid change located in the intracellular domain (Fried 2011) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276498 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 1600 fold above the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype (2.9e-06), strongly suggesting that the variant is benign. Though c.563A>T has been reported in the literature in individual(s) affected with sporadic CVID (Grimbacher 2006), this report does not provide unequivocal conclusions about association of the variant with CVID. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant for protein expression, ligand binding and signaling function (Fried 2011). Three 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Immunodeficiency, common variable, 2

Benign:1

Feb 02, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Uncertain

0.67

D;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.69

N;.

PhyloP100

0.14

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.6

D;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.88

P;P

Vest4

0.42

MVP

0.78

MPC

0.054

ClinPred

0.061

GERP RS

2.4

Varity_R

0.17

gMVP

0.31

Mutation Taster

=98/2

polymorphism

(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