rs77874543

Variant names:

• chr22-41926712-G-C
• rs77874543
• NM_052945.4:c.62C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-41926712-G-C
• chr22-41926712-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_052945.4(TNFRSF13C):​c.62C>G​(p.Pro21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,449,142 control chromosomes in the GnomAD database, including 4,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.056 (301 hom., cov: 32)
  • Exomes 𝑓: 0.076 (3913 hom.)
• Consequence: TNFRSF13C NM_052945.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.668
• Publications: 34 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002217114).
• BP6: Variant 22-41926712-G-C is Benign according to our data. Variant chr22-41926712-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341883.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4	c.62C>G	p.Pro21Arg	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.62C>G	p.Pro21Arg	missense_variant	Exon 1 of 3	1	NM_052945.4	ENSP00000291232.3

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8506 AN: 152018 Hom.: 302 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.0427

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0777

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0607 AC: 4113 AN: 67812 AF XY: 0.0628

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0364

Gnomad ASJ exome AF: 0.0477

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.0806

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0757 AC: 98190 AN: 1297018 Hom.: 3913 Cov.: 33 AF XY: 0.0751 AC XY: 47951 AN XY: 638164

African (AFR) AF: 0.0105 AC: 276 AN: 26168

American (AMR) AF: 0.0430 AC: 1029 AN: 23948

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1095 AN: 22562

East Asian (EAS) AF: 0.0477 AC: 1329 AN: 27888

South Asian (SAS) AF: 0.0610 AC: 4228 AN: 69330

European-Finnish (FIN) AF: 0.0840 AC: 2723 AN: 32400

Middle Eastern (MID) AF: 0.0523 AC: 201 AN: 3844

European-Non Finnish (NFE) AF: 0.0807 AC: 83739 AN: 1037274

Other (OTH) AF: 0.0666 AC: 3570 AN: 53604

GnomAD4 genome AF: 0.0559 AC: 8501 AN: 152124 Hom.: 301 Cov.: 32 AF XY: 0.0556 AC XY: 4133 AN XY: 74366

African (AFR) AF: 0.0136 AC: 566 AN: 41548

American (AMR) AF: 0.0572 AC: 875 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 155 AN: 3472

East Asian (EAS) AF: 0.0429 AC: 220 AN: 5132

South Asian (SAS) AF: 0.0606 AC: 293 AN: 4832

European-Finnish (FIN) AF: 0.0777 AC: 822 AN: 10578

Middle Eastern (MID) AF: 0.0345 AC: 10 AN: 290

European-Non Finnish (NFE) AF: 0.0794 AC: 5398 AN: 67956

Other (OTH) AF: 0.0587 AC: 124 AN: 2112

Alfa AF: 0.0690 Hom.: 59

Bravo AF: 0.0513

TwinsUK AF: 0.0850 AC: 315

ALSPAC AF: 0.0760 AC: 293

ESP6500AA AF: 0.00439 AC: 8

ESP6500EA AF: 0.0319 AC: 118

ExAC AF: 0.0270 AC: 705

Asia WGS AF: 0.0610 AC: 209 AN: 3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31309545, 29867916, 26613719, 27884173, 22699762, 24727458) -

Immunodeficiency, common variable, 4 Benign:3

Apr 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.67
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.026
Sift	Benign	0.27	T
Sift4G	Benign	0.33	T
Polyphen		0.18	B
Vest4		0.032
MPC		1.3
ClinPred		0.00063	T
GERP RS		0.12
PromoterAI		0.022	Neutral
Varity_R		0.13
gMVP		0.047
Mutation Taster		=97/3	polymorphism (auto)

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: rs77874543; hg19: chr22-42322716;