chr22-41926652-G-A

Variant names:

• chr22-41926652-G-A
• rs1556159000
• NM_052945.4:c.122C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052945.4(TNFRSF13C):​c.122C>T​(p.Pro41Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000229 in 1,308,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P41P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TNFRSF13C NM_052945.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21259236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4	c.122C>T	p.Pro41Leu	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	c.122C>T	p.Pro41Leu	missense_variant	Exon 1 of 3	1	NM_052945.4	ENSP00000291232.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1308306 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 644666

African (AFR) AF: 0.00 AC: 0 AN: 26440

American (AMR) AF: 0.00 AC: 0 AN: 25318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22968

East Asian (EAS) AF: 0.000107 AC: 3 AN: 28094

South Asian (SAS) AF: 0.00 AC: 0 AN: 71416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043370

Other (OTH) AF: 0.00 AC: 0 AN: 54082

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 4 Uncertain:1

Jun 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant has uncertain impact on TNFRSF13C function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline with leucine at codon 41 of the TNFRSF13C protein (p.Pro41Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a TNFRSF13C-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0").

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.087
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.052	T
Vest4		0.21
ClinPred		0.58	D
GERP RS		2.5
PromoterAI		-0.081	Neutral
Varity_R		0.51
gMVP		0.071
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1556159000; hg19: chr22-42322656;