rs104894649

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:4

Conservation

PhyloP100: 1.74

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	c.605G>A	p.Arg202His	missense_variant	Exon 4 of 5	ENST00000261652.7	NP_036584.1	O14836-1Q4ACX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7 link	c.605G>A	p.Arg202His	missense_variant	Exon 4 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152164

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000784

AC XY:

106

AN XY:

135180

show subpopulations

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.:

Cov.:

AF XY:

0.000968

AC XY:

704

AN XY:

727038

show subpopulations

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.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74446

show subpopulations

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.:

Bravo

AF:

0.000846

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000766

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 03, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -

Immunodeficiency, common variable, 2

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2025	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2023	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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

-0.059

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.35

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over