22-41925247-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052945.4(TNFRSF13C):c.*120T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,103,354 control chromosomes in the GnomAD database, including 55,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (18242 hom., cov: 32)
  • Exomes 𝑓: 0.25 (37108 hom.)
• Consequence: TNFRSF13C NM_052945.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.681

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-41925247-A-G is Benign according to our data. Variant chr22-41925247-A-G is described in ClinVar as [Benign]. Clinvar id is 341874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13C	NM_052945.4	c.*120T>C		3_prime_UTR_variant	3/3	ENST00000291232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.*120T>C		3_prime_UTR_variant	3/3	1	NM_052945.4	P1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 62078 AN: 152016 Hom.: 18175 Cov.: 32

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.253 AC: 241121 AN: 951220 Hom.: 37108 Cov.: 12 AF XY: 0.254 AC XY: 120678 AN XY: 475028

Gnomad4 AFR exome AF: 0.840

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.409 AC: 62198 AN: 152134 Hom.: 18242 Cov.: 32 AF XY: 0.405 AC XY: 30145 AN XY: 74372

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.371

Alfa AF: 0.304 Hom.: 2346

Bravo AF: 0.448

Asia WGS AF: 0.283 AC: 982 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Immunodeficiency, common variable, 4 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	5.0
Dann	Benign	0.52

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: rs7290134; hg19: chr22-42321251; COSMIC: COSV52170161; COSMIC: COSV52170161;