Genetic Variant NM_052945.4:c.229C>A (chr22-41926239-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_052945.4(TNFRSF13C):c.229C>A(p.Leu77Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L77L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNFRSF13C
NM_052945.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.813

Publications

0 publications found

Variant links:

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)

TNFRSF13C links:

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ACMG classification

Classification was made for transcript

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=0.3688867).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	NM_052945.4	MANE Select	c.229C>A	p.Leu77Met	missense	Exon 2 of 3	NP_443177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13C	ENST00000291232.5	TSL:1 MANE Select	c.229C>A	p.Leu77Met	missense	Exon 2 of 3	ENSP00000291232.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1411382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698986

African (AFR)

AF:

0.00

AC:

AN:

32478

American (AMR)

AF:

0.00

AC:

AN:

39100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

37608

South Asian (SAS)

AF:

0.00

AC:

AN:

81992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091256

Other (OTH)

AF:

0.00

AC:

AN:

58574

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

0.12

Eigen_PC

Benign

0.000073

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PhyloP100

0.81

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.6

REVEL

Benign

0.079

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.28

MutPred

0.28

Loss of stability (P = 0.0937)

MVP

0.37

MPC

1.1

ClinPred

0.75

GERP RS

2.7

Varity_R

0.51

gMVP

0.16

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over