chr22-41925447-G-A

Position:

• chr22-41925447-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_052945.4(TNFRSF13C):​c.475C>T​(p.His159Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00584 in 1,612,458 control chromosomes in the GnomAD database, including 48 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 0.0058 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (45 hom.)
• Consequence: TNFRSF13C NM_052945.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.83

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008018851).
• BP6: Variant 22-41925447-G-A is Benign according to our data. Variant chr22-41925447-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13C	NM_052945.4	c.475C>T	p.His159Tyr	missense_variant	3/3	ENST00000291232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13C	ENST00000291232.5	c.475C>T	p.His159Tyr	missense_variant	3/3	1	NM_052945.4	P1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00825

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00571 AC: 1423 AN: 249214 Hom.: 10 AF XY: 0.00583 AC XY: 788 AN XY: 135116

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00529

Gnomad FIN exome AF: 0.00326

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.00903

GnomAD4 exome AF: 0.00584 AC: 8528 AN: 1460182 Hom.: 45 Cov.: 31 AF XY: 0.00605 AC XY: 4394 AN XY: 726368

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00276

Gnomad4 NFE exome AF: 0.00627

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.00581 AC: 884 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.00540 AC XY: 402 AN XY: 74458

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00825

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00735 Hom.: 8

Bravo AF: 0.00649

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00559 AC: 678

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00871

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	The TNFRSF13C c.475C>T; p.His159Tyr variant (rs61756766) is reported in the literature in multiple individuals affected with various autoimmune diseases, including common variable immunodeficiency (CVID), non-Hodgkin lymphoma, and Sjogren syndrome (Abolhassani 2019, Hildebrand 2010, Kutukculer 2012, Losi 2005, Lougaris 2014, Papageorgiou 2015), but also in healthy controls (Losi 2005, Papageorgiou 2015). Additionally, several of the affected individuals also carried the p.Pro21Arg variant (Kutukculer 2012, Lougaris 2014), including one CVID family in which these two variants were confirmed to be on the same chromosome (Lougaris 2016). This variant is reported in ClinVar (Variation ID: 440345), and is found in the general population with an overall allele frequency of 0.56% (1575/280578 alleles, including 10 homozygotes) in the Genome Aggregation Database. The histidine at codon 159 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show an increase in immunoglobulin production compared to wild-type cells in vitro (Hildebrand 2010), and a reduced amount of protein on patient cells in combination with the p.Pro21Arg variant (Lougaris 2016). Due to conflicting information and the lack of information regarding the association with the p.Pro21Arg variant, the clinical significance of the p.His159Tyr variant alone or in combination with p.Pro21Arg in CVID remains uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

TNFRSF13C: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.58
MVP		0.17
MPC		2.1
ClinPred		0.034	T
GERP RS		5.3
Varity_R		0.81
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61756766; hg19: chr22-42321451;