17-16940415-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1 PM5 PP5 BP4 BS2

The NM_012452.3(TNFRSF13B):c.542C>A(p.Ala181Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,614,040 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (44 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:24 U:1 O:1
• Conservation: PhyloP100: 0.00700

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant 17-16940415-G-T is Pathogenic according to our data. Variant chr17-16940415-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5303.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, not_provided=1, Uncertain_significance=1, Likely_pathogenic=9}. Variant chr17-16940415-G-T is described in Lovd as [Likely_pathogenic]. Variant chr17-16940415-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.08364344).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.542C>A	p.Ala181Glu	missense_variant	4/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.542C>A	p.Ala181Glu	missense_variant	4/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 740 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00533 AC: 1336 AN: 250718 Hom.: 9 AF XY: 0.00526 AC XY: 713 AN XY: 135572

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00544 AC: 7954 AN: 1461766 Hom.: 44 Cov.: 31 AF XY: 0.00532 AC XY: 3867 AN XY: 727176

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0254

Gnomad4 NFE exome AF: 0.00567

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00486 AC: 740 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74454

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.00600

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00364 Hom.: 2

Bravo AF: 0.00321

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00534 AC: 648

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00528

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:24 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:10 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	Commonly occurring variant associated with CVID, observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013); Published functional studies demonstrates the A181E variant introduces a negative charge in the transmembrane domain, which disrupts signaling and impairs B-cell function (Lee et al., 2009); 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: 21850030, 26096648, 19629655, 19779048, 22884984, 27609654, 27123465, 30659808, 31530980, 30843876, 21419480, 19605846, 21547394, 19392801, 22076597, 16007087, 18981294, 23237420, 24051380, 26100089, 17392797, 20156508, 27577878, 16007086, 32581362, 34426522, 30739909, 33046446, 33726816) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 27, 2019	PS3, PS4, PP1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TNFRSF13B: PS3, PP1, PS4:Supporting -

Immunodeficiency, common variable, 2 Pathogenic:7 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 14, 2022	_x000D_ Criteria applied: PS3, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 181 of the TNFRSF13B protein (p.Ala181Glu). This variant is present in population databases (rs72553883, gnomAD 2.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (PMID: 16007086, 16007087, 20156508). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5303). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 19605846, 21419480, 23237420, 24051380). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 08, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PP1 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Established risk allele, no assertion criteria provided	research	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TNFRSF13B c.542C>A (p.Ala181Glu) variant (dbSNP: rs72553883) was identified in ClinVar and was classified as pathogenic x9 (ARUP Laboratories, Centre for Mendelian Genomics University Medical Centre Ljubljana, Baylor, Mayo Clinic, AiLife Diagnostics, Mendelics, GeneDx, OMIM) and likely pathogenic x13 (Genetics Services Laboratory Univerisyt of Chicago, Invitae, LabCorp, Institute of Human Genetics University of Leipzig Medical Center, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, CeGaT Center for Human Genetics Tuebingen, Genome Diagnostics Laboratory University Medical Center Utrecht, Genome Diagnostics Laboratory Amsterdam University Medical Center, Diagnostic Laboratory, Department of Genetics University Medical Center Groningen, Joint Genome Diagnostic Labs from Nijmegen and Maastricht Radboudumc and MUMC+, Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC Erasmus Medical Center) in association with common variable immunodeficiency 2/not provided and likely benign by Illumina in association with dominant common variable immune deficiency (Please refer to ClinVar Accession: VCV000005303.37; Variation ID: 5303 for additional information). The variant was observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013) (verbatim: GeneDx, Accession: SCV000321966.7). In a case-control study of 844 individuals with common variable immune deficiency (CVID) and 3924 controls, this variant was found to be a risk factor for development of CVID (OR 5.60, CI 2.99-10.51) (PMID: 17392797). A meta-analysis of 1,439 CVID patients and 3,558 controls showed that this variant is significantly enriched in CVID patients (PMID: 22884984) (verbatim: Invitae, Accession: SCV000649857.5). The variant was identified in control databases in 1540 of 282092 chromosomes (10 homozygous) at a frequency of 0.005459, and was observed at the highest frequency in the European (Finnish) population in 603 of 24990 chromosomes (freq: 0.02413) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A181 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic- risk factor for common variable immunodeficiency. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Immunoglobulin A deficiency 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 29, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2009	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 01, 2019

The TNFRSF13B c.542C>A; p.Ala181Glu variant (rs72553883) is reported in the literature in multiple individuals diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013). This variant is also observed in clinically asymptomatic relatives and is found in the Finnish European population with an overall allele frequency of 2.4% (603/24990 alleles, including eight homozygotes) in the Genome Aggregation Database, suggesting it may act as a susceptibility or disease-associated variant, possibly with other genetic and/or environmental factors (Dong 2010). Still, case-control studies demonstrate the p.Ala181Glu variant is significantly enriched in affected individuals (OR >5, p< 0.05) (Pan-Hammarstrom 2007, Dong 2010, Freiberger 2012). Functional characterization of the p.Ala181Glu protein in mice (A144E) and human B-cells indicate disrupted NF-KB signaling and significantly impaired B-cell function (Lee 2009, Fried 2011). Based on available information, the variant is considered to be pathogenic. References: Castigli E et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. Dong X et al. (2010) Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B-A181E mutations in common variable immunodeficiency. Hum Immunol. 71(5):505-11. Freiberger T et al. Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. Hum Immunol. 2012 Nov;73(11):1147-54. Fried A et al. Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jul;128(1):226-228.e1. Martinez-Gallo M et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 Feb;131(2):468-76. Lee J et al. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood. 2009 Sep 10;114(11):2254-62. Pan-Hammarstrom Q et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 Apr;39(4):429-30. Salzer U et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 11, 2020

ACMG classification criteria: PS3, PS4, PM3, BS2 -

Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Feb 20, 2022

TNFRSF13B NM_012452.2 exon 4 p.Ala181Glu (c.542C>A): This variant has been reported in the literature in several individuals with features of immunodeficiency and segregating with disease in families, most often Common variable immune deficiency (CVID) (selected publications:Salzer 2005 PMID:16007087, Pan Hammerstrom 2007 PMID:17392797, Lee 2009 PMID:19605846, Dong 2010 PMID:20156508, Freiberger2012 PMID:22884984, Janzi 2012 PMID:21850030, Marinez-Gallo 2013 PMID:23237420 Romberg 2013 PMID:24051380) and this variant is listed as one of the most common variants identified in patients with CVID. This variant is present in 2.4% (603/24990) of Finnish alelles including 8 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16940415-G-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:5303). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies (including a murine model) suggest that this variant impacts the protein (Lee 2009 PMID 19605846, Fried 2011 PMID:21419480, Martinez-Gallo 2013 PMID:23237420, Romberg 2013 PMID:24051380) potentially through impaired expression and signaling. Of note, this variant has been identified in family members who do not present with disease and is present at a high frequency, including homozygotes, in assumed unaffected individuals suggesting notable reduced penetrance and/or variable expressivity. In summary, data on this variant is highly suspicious for disease, but the presence of conflicting data requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

Common variable immunodeficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 01, 2020

Variant summary: TNFRSF13B c.542C>A (p.Ala181Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 250818 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 1864 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), suggesting that the variant is benign. However, this variant has been reported in many individuals with Common Variable Immunodeficiency (CVID, examples: Dong_2010, Castigli_2005, Martinez-Gallo_2013, Salzer_2011, Pomar_2009). These data indicate that the variant is likely to be associated with disease. The variant has been reported in CVID patients as heterozygous, homozygous, and in compound heterozygosity with other pathogenic variants in TNFRSF13B. c.542C>A has been shown to segregate with disease in multiple families (example: Castigli_2005), but has also been observed in unaffected family members (example: Martinez-Gallo_2013), indicating reduced penetrance. Different clinical manifestations have been observed in individuals with the variant, even within the same family (example: Dong_2010). The variant was associated with CVID in a case-control study (OR=5.60, CI 2.99-10.51; Pan-Hammarstrom_2007) and a meta-analysis of cases and controls from the literature (Freiberger_2012). In-vitro functional studies indicated that the variant impaired downstream signaling (example-Fried_2011). In addition, a murine model equivalent to the A181E mutation was assessed as having impaired TACI signaling and function in-vivo (Lee_2009). Six ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments of pathogenic/likely pathogenic (n=4, ) uncertain significance (n=1), likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	12
Dann	Benign	0.80
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.084	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	4.9e-10	A;A;A;A
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.61
Sift	Benign	0.069	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.89	P;P
Vest4		0.47
MVP		0.87
MPC		0.069
ClinPred		0.057	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.46

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

Other links and lift over

dbSNP: rs72553883; hg19: chr17-16843729;