NM_052945.4:c.494C>T

Variant names:

• chr22-41925428-G-A
• NM_052945.4:c.494C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052945.4(TNFRSF13C):​c.494C>T​(p.Ala165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TNFRSF13C NM_052945.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.666
• Publications: 0 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):

• immunodeficiency, common variable, 4

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38960138).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052945.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	NM_052945.4	MANE Select	c.494C>T	p.Ala165Val	missense	Exon 3 of 3	NP_443177.1	Q5H8V1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	ENST00000291232.5	TSL:1 MANE Select	c.494C>T	p.Ala165Val	missense	Exon 3 of 3	ENSP00000291232.3	Q96RJ3-1
	TNFRSF13C	ENST00000898406.1		c.578C>T	p.Ala193Val	missense	Exon 3 of 3	ENSP00000568465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459192 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725888

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency, common variable, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.67
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.11		Loss of loop (P = 0.1242)
MVP		0.65
MPC		1.9
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.18
Mutation Taster		=63/37	polymorphism

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

hg19: chr22-42321432;