chr22-41926712-G-C

Position:

• chr22-41926712-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 -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 id is 341883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr22-41926712-G-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TNFRSF13C	NM_052945.4	c.62C>G	p.Pro21Arg	missense_variant	1/3	ENST00000291232.5	NP_443177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.62C>G	p.Pro21Arg	missense_variant	1/3	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

GnomAD3 exomes AF: 0.0607 AC: 4113 AN: 67812 Hom.: 145 AF XY: 0.0628 AC XY: 2471 AN XY: 39364

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 SAS exome AF: 0.0596

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

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0485

Gnomad4 EAS exome AF: 0.0477

Gnomad4 SAS exome AF: 0.0610

Gnomad4 FIN exome AF: 0.0840

Gnomad4 NFE exome AF: 0.0807

Gnomad4 OTH exome AF: 0.0666

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

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.0606

Gnomad4 FIN AF: 0.0777

Gnomad4 NFE AF: 0.0794

Gnomad4 OTH AF: 0.0587

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2020	This variant is associated with the following publications: (PMID: 31309545, 29867916, 26613719, 27884173, 22699762, 24727458) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -

Immunodeficiency, common variable, 4 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2022	- -

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
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
Varity_R		0.13
gMVP		0.047

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: rs77874543; hg19: chr22-42322716;