Genetic Variant TNFRSF13B:p.Leu162Arg (chr17-16940472-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012452.3(TNFRSF13B):c.485T>G(p.Leu162Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L162L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.39

Publications

0 publications found

Variant links:

Genes affected

TNFRSF13B (HGNC:18153): (TNF receptor superfamily member 13B) The protein encoded by this gene is a lymphocyte-specific member of the tumor necrosis factor (TNF) receptor superfamily. It interacts with calcium-modulator and cyclophilin ligand (CAML). The protein induces activation of the transcription factors NFAT, AP1, and NF-kappa-B and plays a crucial role in humoral immunity by interacting with a TNF ligand. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

TNFRSF13B Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, G2P, Ambry Genetics
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNFRSF13B links:

ENSG00000307457 (HGNC:):

ENSG00000307457 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012452.3. 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
	TNFRSF13B	NM_012452.3	MANE Select	c.485T>G	p.Leu162Arg	missense	Exon 4 of 5	NP_036584.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.485T>G	p.Leu162Arg	missense	Exon 4 of 5	ENSP00000261652.2
TNFRSF13B	ENST00000583789.1	TSL:1	c.347T>G	p.Leu116Arg	missense	Exon 3 of 4	ENSP00000462952.1
TNFRSF13B	ENST00000579009.1	TSL:6	n.591T>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.2

PhyloP100

2.4

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.93

MutPred

0.59

Loss of sheet (P = 0.0142)

MVP

0.91

MPC

0.083

ClinPred

0.93

GERP RS

3.4

Varity_R

0.54

gMVP

0.56

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over