Genetic Variant TNFRSF13B:p.Ala239Gly (chr17-16939713-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012452.3(TNFRSF13B):c.716C>G(p.Ala239Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A239V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNFRSF13B
NM_012452.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.682

Publications

1 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0797151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3 link	c.716C>G	p.Ala239Gly	missense_variant	Exon 5 of 5	ENST00000261652.7	NP_036584.1	O14836-1Q4ACX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7 link	c.716C>G	p.Ala239Gly	missense_variant	Exon 5 of 5	1	NM_012452.3	ENSP00000261652.2		O14836-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454094

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106920

Other (OTH)

AF:

0.00

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.6

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.55

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.080

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.2

L;.

PhyloP100

0.68

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.26

Sift

Benign

0.10

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.42

B;P

Vest4

0.092

MutPred

0.13

Loss of stability (P = 0.0341);.;

MVP

0.60

MPC

0.021

ClinPred

0.17

GERP RS

-1.3

Varity_R

0.062

gMVP

0.077

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over