NM_012452.3:c.310T>C

Variant names:

• chr17-16948873-A-G
• rs34557412
• NM_012452.3:c.310T>C
• TNFRSF13B p.Cys104Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3 PM5 PP5 BP4

The NM_012452.3(TNFRSF13B):​c.310T>C​(p.Cys104Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00544 in 1,614,226 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). ClinVar reports functional evidence for this variant: "SCV000649856: Experimental studies have shown that this missense change affects TNFRSF13B function (PMID:16007087, 20889194, 21419480, 21458042, 23237420, 24051380)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C104Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (28 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:41 U:5 B:1 O:2
• Conservation: PhyloP100: 4.18
• Publications: 157 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000649856: Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 16007087, 20889194, 21419480, 21458042, 23237420, 24051380).; SCV002058245: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20889194, 21419480).; SCV005685537: "In vitro functional studies and murine models demonstrate that the variant results in impaired downstream signaling (Bacchelli C et al., PMID: 21458042; Lee JJ et al., PMID: 20889194; Martinez-Gallo M et al., PMID: 23237420; Salzer U et al., PMID: 18981294)."; SCV000329550: Published functional studies demonstrate C104R results in reduced surface expression and elimination of ligand binding, supporting a damaging effect (Lee et al., 2010; Fried et al., 2011); SCV000605391: Additionally, functional studies show that this variant disrupts protein signaling (Martinez-Gallo 2013, Salzer 2005).; SCV002070496: Functional studies have demonstrated that this sequence change affects ligand binding and reduces protein expression (PMID: 16007087, 21419480, 23237420).; SCV000699342: Multiple experimental studies suggest the variant causes significant defects to protein function. Specifically, protein expression and ligand binding were demonstrated to be significantly diminished (Bacchelli_2011, Salzer_2005).; SCV002495994: Numerous functional studies including mouse models have demonstrated the impact of this variant by reducing expression on the surface of B-cells, impairing bindings with BAFF and APRIL and defective antibody production (Salzer 2005 PMID:16007087, Lee 2010 PMID:20889194, Fried 2011 PMID:21419480, Martinez-Galllo 2013 PMID:23237420).; SCV004046269: "In-vitro studies showed that this variant disrupts NF-κB/NF-AT signaling and leads to defective B-cell proliferation in response to stimulation." PMID:21419480, 23237420, 19605846; SCV004104594: Functional studies have shown the p.Cys104Arg variant impairs TACI ligand binding and B-cell function (Romberg et al. 2015. PubMed ID: 26100089; Lee et al. 2010. PubMed ID: 20889194).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-16948872-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 645207.
• PP5: Variant 17-16948873-A-G is Pathogenic according to our data. Variant chr17-16948873-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 5302.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23062569). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012452.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	NM_012452.3	MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	NP_036584.1	O14836-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	ENSP00000261652.2	O14836-1
	TNFRSF13B	ENST00000583789.1	TSL:1	c.172T>C	p.Cys58Arg	missense	Exon 2 of 4	ENSP00000462952.1	O14836-2
	TNFRSF13B	ENST00000579315.5	TSL:3	c.310T>C	p.Cys104Arg	missense	Exon 3 of 4	ENSP00000464069.1	J3QR67

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00350 AC: 879 AN: 251490 AF XY: 0.00343

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00560 AC: 8186 AN: 1461892 Hom.: 28 Cov.: 35 AF XY: 0.00533 AC XY: 3875 AN XY: 727246

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00416 AC: 186 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86258

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00675 AC: 7506 AN: 1112010

Other (OTH) AF: 0.00477 AC: 288 AN: 60396

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74502

African (AFR) AF: 0.00147 AC: 61 AN: 41584

American (AMR) AF: 0.00713 AC: 109 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00579 AC: 394 AN: 68018

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00485 Hom.: 2

Bravo AF: 0.00422

EpiCase AF: 0.00627

EpiControl AF: 0.00605

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
19	2	-	Immunodeficiency, common variable, 2 (23)
13	2	1	not provided (16)
2	-	-	TNFRSF13B-related disorder (2)
1	-	-	Common variable immunodeficiency (1)
1	-	-	Immune deficiency, familial variable (1)
1	-	-	Immunodeficiency, common variable, 1 (1)
1	-	-	Immunoglobulin A deficiency 2 (1)
1	-	-	Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 (1)
-	1	-	not specified (1)
1	-	-	Severe SARS-CoV-2 infection, susceptibility to (1)
-	-	-	Immunodeficiency, common variable, 1;C3150354:Immunodeficiency, common variable, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	26
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.96
gMVP		0.67
Mutation Taster		=21/79	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34557412; hg19: chr17-16852187; COSMIC: COSV55430181;