17-16939564-C-T

Position:

• chr17-16939564-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012452.3(TNFRSF13B):​c.865G>A​(p.Gly289Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036928058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3	c.865G>A	p.Gly289Arg	missense_variant	5/5	ENST00000261652.7	NP_036584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.865G>A	p.Gly289Arg	missense_variant	5/5	1	NM_012452.3	ENSP00000261652	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 28, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 289 of the TNFRSF13B protein (p.Gly289Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNFRSF13B-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	13
DANN	Benign	0.66
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.22
Sift	Benign	0.57	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.0050	B;B
Vest4		0.076
MutPred		0.22		Loss of catalytic residue at P285 (P = 0.0708);.;
MVP		0.39
MPC		0.069
ClinPred		0.082	T
GERP RS		-1.8
Varity_R		0.061
gMVP		0.085

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-16842878;