rs764125338

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012452.3(TNFRSF13B):c.577T>C(p.Cys193Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.428

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08151394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3 linkuse as main transcript	c.577T>C	p.Cys193Arg	missense_variant	4/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7 linkuse as main transcript	c.577T>C	p.Cys193Arg	missense_variant	4/5	1	NM_012452.3	P2	O14836-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250588

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2017	The C193R variant in the TNFRSF13B gene has been reported previously in an individual with features of both autoimmune lymphoproliferative syndrome and CVID; however, this individual also harbored a variant in the CASP9 gene that may also have contributed to the phenotype (Clemente et al., 2015). Additionally, this individual harbored a nonsense variant on the same TNFRSF13B allele (in cis). The C193R variant is observed in 6/66,548 (0.009%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The C193R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret C193R as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -

Immunodeficiency, common variable, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 193 of the TNFRSF13B protein (p.Cys193Arg). This variant is present in population databases (rs764125338, gnomAD 0.01%). This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome and/or common variable immunodeficiency (PMID: 25569260, 33859323). ClinVar contains an entry for this variant (Variation ID: 449227). 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 not expected to disrupt TNFRSF13B protein function with a negative predictive value of 80%. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.19

Cadd

Benign

1.3

Dann

Benign

0.51

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.0

D;.

REVEL

Uncertain

0.34

Sift

Benign

0.18

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.54

P;P

Vest4

0.15

MutPred

0.25

Loss of catalytic residue at P192 (P = 0.0079);.;

MVP

0.31

MPC

0.016

ClinPred

0.10

GERP RS

-4.1

Varity_R

0.27

gMVP

0.12

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

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