Genetic Variant TNFRSF13C:p.Pro21Gln (chr22-41926712-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052945.4(TNFRSF13C):c.62C>A(p.Pro21Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P21R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNFRSF13C
NM_052945.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.668

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency, common variable, 4
Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

TNFRSF13C links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04172349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4 link	c.62C>A	p.Pro21Gln	missense_variant	Exon 1 of 3	ENST00000291232.5	NP_443177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13C	ENST00000291232.5 link	c.62C>A	p.Pro21Gln	missense_variant	Exon 1 of 3	1	NM_052945.4	ENSP00000291232.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1297242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

638296

African (AFR)

AF:

0.00

AC:

AN:

26168

American (AMR)

AF:

0.00

AC:

AN:

23958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22568

East Asian (EAS)

AF:

0.00

AC:

AN:

27888

South Asian (SAS)

AF:

0.00

AC:

AN:

69362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3844

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1037432

Other (OTH)

AF:

0.00

AC:

AN:

53614

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.096

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.32

M_CAP

Benign

0.0064

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-0.67

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.93

REVEL

Benign

0.017

Sift

Benign

1.0

Sift4G

Benign

0.72

Polyphen

0.0020

Vest4

0.12

MutPred

0.42

Loss of loop (P = 0.0389);

MVP

0.043

MPC

0.76

ClinPred

0.065

GERP RS

0.12

PromoterAI

0.053

Neutral

(source)

Varity_R

0.073

gMVP

0.046

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over