rs72553876

chr17-16948947-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3 PP5

The NM_012452.3(TNFRSF13B):c.236A>G(p.Tyr79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,188 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).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 3.58

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 4 ACMG points.

• PM1: In a repeat TNFR-Cys 2 (size 34) in uniprot entity TR13B_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_012452.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• PP5: Variant 17-16948947-T-C is Pathogenic according to our data. Variant chr17-16948947-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=4}. Variant chr17-16948947-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.236A>G	p.Tyr79Cys	missense_variant	3/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.236A>G	p.Tyr79Cys	missense_variant	3/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.000176

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251394 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

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: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461890 Hom.: 0 Cov.: 35 AF XY: 0.000268 AC XY: 195 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000322

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74460

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2023	Identified in the presence of a second TNFRSF13B variant in siblings with IgG subclass deficiency, one of whom had recurrent infections requiring IVIG therapy; however, their heterozygous mother was unaffected and father with dysgammaglobulinemia or IgG subclass deficiency was not tested (Salzer et al., 2009); Identified heterozygous in a patient with a personal history suggestive of common variable immune deficiency in published literature, though clinical details and segregation information were not provided (Hou et al., 2020); Identified heterozygous in a patient with recurrent pneumonia, recurrent gastroenteritis, and chronic oral herpes lesions in published literature, though segregation information was not provided (Engelbrecht et al., 2021); Surface expression studies support that the Y79C variant is damaging to the TNFRSF13B protein (Fried et al., 2011); 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: 18954329, 21458042, 22884984, 18981294, 32581362, 21419480, 34093558, 31980526) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -

not specified Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2017	- -

Immunodeficiency, common variable, 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the TNFRSF13B protein (p.Tyr79Cys). This variant is present in population databases (rs72553876, gnomAD 0.05%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID), IgG subclass deficiency, and/or primary immune disorders (PMID: 18981294, 22884984, 32581362, 34093558). ClinVar contains an entry for this variant (Variation ID: 281110). 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: 18954329, 21419480, 21458042). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 01, 2021	ACMG classification criteria: PS3 supporting, PM3 supporting, PP3 -

TNFRSF13B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2023

The TNFRSF13B c.236A>G variant is predicted to result in the amino acid substitution p.Tyr79Cys. This variant has been reported in the compound heterozygous state in two individuals with IgG subclass deficiency from the same family (Salzer et al. 2009. PubMed ID: 18981294). Of note, this variant was also seen in the heterozygous state in a healthy member of that same family (Salzer et al. 2009. PubMed ID: 18981294). Functional analysis showed that the c.236A>G variant leads to a reduction in protein activity as compared to wild-type (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	25
Dann	Benign	0.89
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.83
MVP		0.89
MPC		0.084
ClinPred		0.48	T
GERP RS		5.0
Varity_R		0.82
gMVP		0.66

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: rs72553876; hg19: chr17-16852261;