rs140820836

chr22-41926239-G-Achr22-41926239-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_052945.4(TNFRSF13C):c.229C>T(p.Leu77=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,563,654 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L77L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: TNFRSF13C NM_052945.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.813

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-41926239-G-A is Benign according to our data. Variant chr22-41926239-G-A is described in ClinVar as [Benign]. Clinvar id is 487214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.813 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1615/152272) while in subpopulation AFR AF= 0.0379 (1577/41564). AF 95% confidence interval is 0.0364. There are 32 homozygotes in gnomad4. There are 779 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13C	NM_052945.4	c.229C>T	p.Leu77=	synonymous_variant	2/3	ENST00000291232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.229C>T	p.Leu77=	synonymous_variant	2/3	1	NM_052945.4	P1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 152164 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00242 AC: 397 AN: 163878 Hom.: 10 AF XY: 0.00186 AC XY: 169 AN XY: 90674

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00105 AC: 1487 AN: 1411382 Hom.: 31 Cov.: 33 AF XY: 0.000927 AC XY: 648 AN XY: 698986

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.000614

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000488

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000751

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.0106 AC: 1615 AN: 152272 Hom.: 32 Cov.: 32 AF XY: 0.0105 AC XY: 779 AN XY: 74448

Gnomad4 AFR AF: 0.0379

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000495 Hom.: 0

Bravo AF: 0.0116

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 4 Benign:3

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 12, 2018	- -

TNFRSF13C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.8
Dann	Benign	0.83

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: rs140820836; hg19: chr22-42322243;