chr22-41925447-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_052945.4(TNFRSF13C):c.475C>T(p.His159Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00584 in 1,612,458 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 45 hom. )

Consequence

TNFRSF13C
NM_052945.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

TNFRSF13C (HGNC:17755): (TNF receptor superfamily member 13C) B cell-activating factor (BAFF) enhances B-cell survival in vitro and is a regulator of the peripheral B-cell population. Overexpression of Baff in mice results in mature B-cell hyperplasia and symptoms of systemic lupus erythematosus (SLE). Also, some SLE patients have increased levels of BAFF in serum. Therefore, it has been proposed that abnormally high levels of BAFF may contribute to the pathogenesis of autoimmune diseases by enhancing the survival of autoreactive B cells. The protein encoded by this gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular cysteine-rich domain. It is thought that this receptor is the principal receptor required for BAFF-mediated mature B-cell survival. [provided by RefSeq, Jul 2008]

TNFRSF13C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008018851).

BP6

Variant 22-41925447-G-A is Benign according to our data. Variant chr22-41925447-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440345.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4 link	c.475C>T	p.His159Tyr	missense_variant	Exon 3 of 3	ENST00000291232.5	NP_443177.1	Q96RJ3-1Q5H8V1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13C	ENST00000291232.5 link	c.475C>T	p.His159Tyr	missense_variant	Exon 3 of 3	1	NM_052945.4	ENSP00000291232.3		Q96RJ3-1

Frequencies

GnomAD3 genomes

AF:

0.00581

AC:

884

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00825

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00571

AC:

1423

AN:

249214

Hom.:

AF XY:

0.00583

AC XY:

788

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.00329

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00529

Gnomad FIN exome

AF:

0.00326

Gnomad NFE exome

AF:

0.00749

Gnomad OTH exome

AF:

0.00903

GnomAD4 exome

AF:

0.00584

AC:

8528

AN:

1460182

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4394

AN XY:

726368

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00709

Gnomad4 ASJ exome

AF:

0.00467

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00533

Gnomad4 FIN exome

AF:

0.00276

Gnomad4 NFE exome

AF:

0.00627

Gnomad4 OTH exome

AF:

0.00626

GnomAD4 genome

AF:

0.00581

AC:

884

AN:

152276

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00825

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00735

Hom.:

Bravo

AF:

0.00649

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00559

AC:

678

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00871

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 4

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	The TNFRSF13C c.475C>T; p.His159Tyr variant (rs61756766) is reported in the literature in multiple individuals affected with various autoimmune diseases, including common variable immunodeficiency (CVID), non-Hodgkin lymphoma, and Sjogren syndrome (Abolhassani 2019, Hildebrand 2010, Kutukculer 2012, Losi 2005, Lougaris 2014, Papageorgiou 2015), but also in healthy controls (Losi 2005, Papageorgiou 2015). Additionally, several of the affected individuals also carried the p.Pro21Arg variant (Kutukculer 2012, Lougaris 2014), including one CVID family in which these two variants were confirmed to be on the same chromosome (Lougaris 2016). This variant is reported in ClinVar (Variation ID: 440345), and is found in the general population with an overall allele frequency of 0.56% (1575/280578 alleles, including 10 homozygotes) in the Genome Aggregation Database. The histidine at codon 159 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show an increase in immunoglobulin production compared to wild-type cells in vitro (Hildebrand 2010), and a reduced amount of protein on patient cells in combination with the p.Pro21Arg variant (Lougaris 2016). Due to conflicting information and the lack of information regarding the association with the p.Pro21Arg variant, the clinical significance of the p.His159Tyr variant alone or in combination with p.Pro21Arg in CVID remains uncertain. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2025

TNFRSF13C: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.58

MVP

0.17

MPC

2.1

ClinPred

0.034

GERP RS

5.3

Varity_R

0.81

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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