rs751216929

Positions:

• chr17-16940442-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_012452.3(TNFRSF13B):​c.515G>A​(p.Cys172Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.94

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_012452.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.515G>A	p.Cys172Tyr	missense_variant	4/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.515G>A	p.Cys172Tyr	missense_variant	4/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000865

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: 0.000183 AC: 46 AN: 250698 Hom.: 1 AF XY: 0.000221 AC XY: 30 AN XY: 135572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461676 Hom.: 1 Cov.: 31 AF XY: 0.000164 AC XY: 119 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000865

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: 0.000250 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 23, 2021	ACMG classification criteria: PP3 supporting, BS1 strong -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 172 of the TNFRSF13B protein (p.Cys172Tyr). This variant is present in population databases (rs751216929, gnomAD 0.04%). This missense change has been observed in individual(s) with TNFRSF13B-related disease (PMID: 17983875, 19629655, 27123465). ClinVar contains an entry for this variant (Variation ID: 449548). 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	Published functional studies demonstrate a damaging effect (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: 17983875, 27123465, 21419480, 19629655, 31530980, 33206719) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TNFRSF13B: PS3:Moderate, PM2:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Uncertain	0.77	D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.59	D;D;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-10	D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;D
Vest4		0.54
MVP		0.84
MPC		0.082
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.94
gMVP		0.37

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: rs751216929; hg19: chr17-16843756;