rs547352394

chr22-41926277-C-Achr22-41926277-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_052945.4(TNFRSF13C):c.191G>T(p.Gly64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,488,228 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G64S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (119 hom.)
• Consequence: TNFRSF13C NM_052945.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.300

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050999224).
• BP6: Variant 22-41926277-C-A is Benign according to our data. Variant chr22-41926277-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440343.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13C	NM_052945.4	c.191G>T	p.Gly64Val	missense_variant	2/3	ENST00000291232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.191G>T	p.Gly64Val	missense_variant	2/3	1	NM_052945.4	P1

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 1085 AN: 152044 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00586

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00868 AC: 787 AN: 90680 Hom.: 14 AF XY: 0.00799 AC XY: 411 AN XY: 51458

Gnomad AFR exome AF: 0.00331

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00283

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0107 AC: 14316 AN: 1336076 Hom.: 119 Cov.: 33 AF XY: 0.0105 AC XY: 6934 AN XY: 658982

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00810

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00853

GnomAD4 genome AF: 0.00712 AC: 1083 AN: 152152 Hom.: 6 Cov.: 32 AF XY: 0.00646 AC XY: 481 AN XY: 74406

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00586

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0102 Hom.: 4

Bravo AF: 0.00642

ExAC AF: 0.00674 AC: 189

Asia WGS AF: 0.00117 AC: 4 AN: 3448

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 4 Uncertain:1 Benign:3

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 30, 2020	The TNFRSF13C c.191G>T variant is classified as Likely Benign (BS1, BP6) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TNFRSF13C: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.030
Sift	Benign	0.059	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.011	B
Vest4		0.33
MVP		0.043
MPC		2.1
ClinPred		0.044	T
GERP RS		0.97
Varity_R		0.24
gMVP		0.22

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

Other links and lift over

dbSNP: rs547352394; hg19: chr22-42322281;