rs150374940

Positions:

chr22-41926151-C-T

Variant summary

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

The ENST00000291232.5(TNFRSF13C):c.317G>A(p.Arg106Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,611,928 control chromosomes in the GnomAD database, including 16 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 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

TNFRSF13C
ENST00000291232.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -2.50

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=0.005455345).

BP6

Variant 22-41926151-C-T is Benign according to our data. Variant chr22-41926151-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341877.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2}. Variant chr22-41926151-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4 linkuse as main transcript	c.317G>A	p.Arg106Gln	missense_variant	2/3	ENST00000291232.5	NP_443177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF13C	ENST00000291232.5 linkuse as main transcript	c.317G>A	p.Arg106Gln	missense_variant	2/3	1	NM_052945.4	ENSP00000291232	P1	Q96RJ3-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00181

AC:

431

AN:

237694

Hom.:

AF XY:

0.00189

AC XY:

248

AN XY:

131282

show subpopulations

Gnomad AFR exome

AF:

0.000794

Gnomad AMR exome

AF:

0.000380

Gnomad ASJ exome

AF:

0.000204

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000967

Gnomad NFE exome

AF:

0.00364

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.00352

AC:

5143

AN:

1459568

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

2449

AN XY:

726174

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00443

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00189

AC:

288

AN:

152360

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00348

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00206

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.00331

AC:

ExAC

AF:

0.00183

AC:

217

EpiCase

AF:

0.00387

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 4

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Apr 26, 2022	TNFRSF13C NM_052945.3 exon 2 p.Arg106Gln (c.317G>A): This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.3% (237/68040) (https://gnomad.broadinstitute.org/variant/22-41926151-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign (Variation ID:341877). This variant amino acid Glutamine (Gln) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

Immunodeficiency, common variable, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 26, 2018

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

TNFRSF13C: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.17

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.47

M_CAP

Benign

0.0065

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

REVEL

Benign

0.022

Sift

Benign

0.51

Sift4G

Benign

0.51

Polyphen

0.0070

Vest4

0.14

MVP

0.082

MPC

0.94

ClinPred

0.024

GERP RS

-0.56

Varity_R

0.029

gMVP

0.13

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

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