rs104894649

Variant names:

• chr17-16940352-C-T
• rs104894649
• NM_012452.3:c.605G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_012452.3(TNFRSF13B):​c.605G>A​(p.Arg202His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000969 in 1,613,764 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:4
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23804653).
• BP6: Variant 17-16940352-C-T is Benign according to our data. Variant chr17-16940352-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5304.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000729 (111/152282) while in subpopulation NFE AF= 0.00119 (81/68022). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3	c.605G>A	p.Arg202His	missense_variant	Exon 4 of 5	ENST00000261652.7	NP_036584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.605G>A	p.Arg202His	missense_variant	Exon 4 of 5	1	NM_012452.3	ENSP00000261652.2

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000796 AC: 199 AN: 249890 Hom.: 0 AF XY: 0.000784 AC XY: 106 AN XY: 135180

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000994 AC: 1452 AN: 1461482 Hom.: 1 Cov.: 31 AF XY: 0.000968 AC XY: 704 AN XY: 727038

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74446

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00104

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Sep 03, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNFRSF13B c.605G>A; p.Arg202His variant (rs104894649) is reported in literature in six individuals affected with common variable immune deficiency (Janzi 2012, Pan-Hammarström 2007, Salzer 2005) and two individuals with IgAD (Pan-Hammarström 2007). This variant was more frequently observed in control individuals compared to CVID cohort, though an enrichment was observed in IgAD cohort compared to controls with an odds ratio of 5.91 (1.94~18.07, 95% CI) (Pan-Hammarström 2007). Data obtained from a single IgAD patient suggested that this variant does not alter IgA levels (Janzi 2012). Functional analyses of the variant protein by luciferase reporter assay showed no impact on downstream signaling pathway components (He 2010). This variant is also reported in ClinVar (Variation ID: 5304). This variant is found in the non-Finnish European population with an allele frequency of 0.12% (156/127656 alleles) in the Genome Aggregation Database. The arginine at codon 202 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.554). Due to conflicting information, the clinical significance of this variant is uncertain at this time. -

Jun 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as a single heterozygous variant in patients with common variable immune deficiency (CVID) in the published literature; however also found at a similar frequency in controls, suggesting R202H may not contribute to risk of CVID (Salzer et al., 2005; Castigli et al., 2005; Pan-Hammarstrm et al., 2007; Freiberger et al., 2012); Published functional studies demonstrate no damaging effect, as R202H retained NF-kB activation and ligand binding (Bacchelli et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16007087, 16007086, 23956760, 21850030, 22884984, 19392801, 34426522, 21458042, 17392797, 30090215, 30269248, 33206719, 35655776) -

Nov 30, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency, common variable, 2 Pathogenic:1 Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:2

Jun 25, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF13B c.605G>A (p.Arg202His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 249890 control chromosomes. The observed variant frequency is approximately 278.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), strongly suggesting that the variant is benign. c.605G>A has been reported in the literature in individuals affected with Common Variable Immunodeficiency and IgA deficiency, however without strong supporting evidence of pathogenicity and often also being found in controls (Castigli_2005, Salzar_2005, Castigli_2007, Lopez-Mejias_2009, Freiberger_2012, DeVries_2011, Karaca_2018, Pulvirenti_2016). The variant has been reported to not segregate with disease in 3 families, including the variant being found in unaffected family members and affected family members lacking the variant (Pan-Hammarstrom_2007, Speletas_2011). Experimental evidence showed the variant had little or no inhibitory effect on signaling via NF-kB and AP-1 and did not impair the interaction with MyD88, TRAF2, TRAF5, TRAF6 or CAML (He_2010). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two labs classified the variant as benign/likely benign while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 07, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg202His variant in TNFRSF13B has been reported in multiple individuals with combined immunodeficiency or IgA deficiency, however it has also been found at similar frequencies in control populations and was not found to segregate with individuals in a family (Pan-Hammarstrom 2007 PMID: 17392797, Lopez-Mejias 2009 PMID: 19392801, Janzi 2012 PMID: 21850030, Speletas 2013 PMID: 23956760, van Schouwenburg 2015 PMID: 26122175). This variant has been identified in 0.14% (5/3468) of Ashkenazi Jewish and 0.1% (81/68030) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v 3.1.2). This variant has also been reported in ClinVar (Variation ID 5304). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant does not impact protein function (Bacchelli 2011 PMID: 21458042, He 2010 PMID: 20676093); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign/its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS3_Moderate, BS4_Supporting. -

Common Variable Immune Deficiency, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.69	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.20	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.47	P;B
Vest4		0.27
MVP		0.70
MPC		0.033
ClinPred		0.0097	T
GERP RS		2.0
Varity_R		0.058
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894649; hg19: chr17-16843666;