22-41926714-G-A

Position:

• chr22-41926714-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_052945.4(TNFRSF13C):​c.60C>T​(p.Val20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,449,040 control chromosomes in the GnomAD database, including 40 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 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (40 hom.)
• Consequence: TNFRSF13C NM_052945.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.168

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-41926714-G-A is Benign according to our data. Variant chr22-41926714-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440344.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr22-41926714-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.168 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13C	NM_052945.4	c.60C>T	p.Val20=	synonymous_variant	1/3	ENST00000291232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.60C>T	p.Val20=	synonymous_variant	1/3	1	NM_052945.4	P1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00674

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00377 AC: 254 AN: 67386 Hom.: 3 AF XY: 0.00332 AC XY: 130 AN XY: 39132

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.000860

Gnomad ASJ exome AF: 0.00168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00823

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00607 AC: 7872 AN: 1296828 Hom.: 40 Cov.: 33 AF XY: 0.00587 AC XY: 3745 AN XY: 638150

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00160

Gnomad4 EAS exome AF: 0.0000358

Gnomad4 SAS exome AF: 0.000896

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00722

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74424

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00674

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.000869 AC: 3 AN: 3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 4 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

TNFRSF13C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

TNFRSF13C: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.93

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: rs373828157; hg19: chr22-42322718;