17-16972018-G-A

Position:

chr17-16972018-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012452.3(TNFRSF13B):c.58C>T(p.Arg20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.341

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:

TNFRSF13B (HGNC:):

TNFRSF13B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060708642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 linkuse as main transcript	c.58C>T	p.Arg20Cys	missense_variant	1/5	ENST00000261652.7	NP_036584.1	O14836-1Q4ACX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7 linkuse as main transcript	c.58C>T	p.Arg20Cys	missense_variant	1/5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251286

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1461766

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000125

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Micrognathia;C0036572:Seizure;C0221263:Cafe-au-lait spot;C0221354:Frontal bossing;C0239676:High forehead;C0338656:Cognitive impairment;C1857790:Thoracic scoliosis;C4022745:Abnormal basal ganglia MRI signal intensity;C4520981:Abnormal basal ganglia morphology

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Immunodeficiency, common variable, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 20 of the TNFRSF13B protein (p.Arg20Cys). This variant is present in population databases (rs200013015, gnomAD 0.03%). This missense change has been observed in individual(s) with systemic lupus erythematosus (SLE) and hyper-IgM syndrome or common variable immunodeficiency (PMID: 17464555, 20652909, 33859323, 34441032). ClinVar contains an entry for this variant (Variation ID: 577672). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 23, 2021

The inherited heterozygous c.58C>T (p.Arg20Cys) missense variant identified in the TNFRSF13B gene has been reported in a patient affected with hyper-IgM syndrome or common variable immunodeficiency [PMID: 20652909], and in another individual affected with systemic lupus erythematosus (but didn't co-segregate with the disease in that family [PMID: 17464555]. This variant has been reported in ClinVar database as a variant of uncertain significance [Variation ID: 577672]. The variant has 0.0001249 allele frequency in the gnomAD database (19 out of 152,114 heterozygous alleles, no homozygotes) indicating it is not a benign polymorphism in the populations represented in that database. The variant affects a weakly conserved reside and in silico tools provide conflicting interpretations about potential pathogenicity of this variant. Due to the lack of compelling evidence for its pathogenicity, the inherited heterozygous c.58C>T (p.Arg20Cys) missense variant identified in the TNFRSF13B gene of this individual is reported as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.63

.;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.040

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.81, 0.88

.;P;P

Vest4

0.32

MVP

0.70

MPC

0.014

ClinPred

0.032

GERP RS

-1.7

Varity_R

0.067

gMVP

0.16

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