rs143027621

Positions:

chr17-16940445-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_012452.3(TNFRSF13B):c.512T>G(p.Leu171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L171L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 1.69

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_pathogenic. Variant got 7 ACMG points.

PM1

In a transmembrane_region Helical; Signal-anchor for type III membrane protein (size 20) in uniprot entity TR13B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_012452.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 17-16940445-A-C is Pathogenic according to our data. Variant chr17-16940445-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440340.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=4}. Variant chr17-16940445-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3 linkuse as main transcript	c.512T>G	p.Leu171Arg	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.512T>G	p.Leu171Arg	missense_variant	4/5	1	NM_012452.3	P2	O14836-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

250756

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000176

AC:

257

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000138

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0216

Hom.:

2154

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 22, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	Published functional studies demonstrate unstable protein with negligible ligand binding (PMID: 21419480); Reported in an individual with lower respiratory track infections, HSV infections, and giardiasis; however her heterozygous mother was reportedly healthy and the variant did not segregate with autoimmunity, vitiligo, and thyroiditis in the extended family members (PMID: 22697072); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17983875, 37711607, 35570134, 34247095, 32344018, 19779048, 23237420, 17392798, 31530980, 32581362, 21419480, 22697072) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2021	PS3, PP3 -

Immunodeficiency, common variable, 2

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 171 of the TNFRSF13B protein (p.Leu171Arg). This variant is present in population databases (rs143027621, gnomAD 0.02%). This variant has been reported as homozygous, compound heterozygous, and heterozygous in individuals and families affected with common variable immunodeficiency (PMID: 17983875, 17392798, 19779048, 22697072, 23237420, 32581362, 31530980). It has also been observed as heterozygous in asymptomatic individuals from these same families (PMID: 23237420, 22697072). ClinVar contains an entry for this variant (Variation ID: 440340). ClinVar contains an entry for this variant (Variation ID: 440340). 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 expected to disrupt TNFRSF13B protein function. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 21419480). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 09, 2022	ACMG classification criteria: PS3 supporting, PM3 strong, PP3 supporting -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 03, 2017

- -

TNFRSF13B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The TNFRSF13B c.512T>G variant is predicted to result in the amino acid substitution p.Leu171Arg. This variant has been reported in the homozygous, compound heterozygous and heterozygous states in individuals with common variable immunodeficiency (Castigli et al. 2007. PubMed ID: 17392798; Zhang et al. 2007. PubMed ID: 17983875; Martínez-Pomar et al. 2009. PubMed ID: 19779048; Barroeta Seijas et al. 2012. PubMed ID: 22697072; Martinez-Gallo et al. 2013. PubMed ID: 23237420). This variant has also been observed in the heterozygous state in asymptomatic individuals (Family of patient C.I - father C.II and sister C.III, Martinez-Gallo et al. 2013. PubMed ID: 23237420). The variant did not segregate with disease in another family with autoimmunity, vitiligo, and thyroiditis (Family C, Barroeta Seijas et al. 2012. PubMed ID: 22697072). Of note, in that family all members (mother, father, sister, and proband) were reported healthy, but had symptoms of autoimmune diseases; however only the proband was diagnosed with common variable immunodeficiency. Functional studies demonstrated that the p.Leu171Arg variant impacted the expression and function of the TNFRSF13B protein (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations in the ClinVar database, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/440340/). While this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Uncertain

0.76

D;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

0.73

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.6

D;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.84

MVP

0.84

MPC

0.083

ClinPred

0.80

GERP RS

3.4

Varity_R

0.63

gMVP

0.63

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