rs74811083

chr17-16940394-T-Achr17-16940394-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012452.3(TNFRSF13B):c.563A>T(p.Lys188Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,611,408 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K188N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (60 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.140

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057032406).
• BP6: Variant 17-16940394-T-A is Benign according to our data. Variant chr17-16940394-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 235322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.563A>T	p.Lys188Met	missense_variant	4/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.563A>T	p.Lys188Met	missense_variant	4/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2206 AN: 151892 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000646

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00346 AC: 868 AN: 250762 Hom.: 16 AF XY: 0.00249 AC XY: 338 AN XY: 135572

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00144 AC: 2107 AN: 1459396 Hom.: 60 Cov.: 31 AF XY: 0.00123 AC XY: 891 AN XY: 725466

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000714

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.0145 AC: 2207 AN: 152012 Hom.: 52 Cov.: 32 AF XY: 0.0137 AC XY: 1017 AN XY: 74290

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000646

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00997

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.0158

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0493 AC: 217

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00463 AC: 560

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 22, 2018

Variant summary: TNFRSF13B c.563A>T (p.Lys188Met) results in a non-conservative amino acid change located in the intracellular domain (Fried 2011) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276498 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 1600 fold above the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype (2.9e-06), strongly suggesting that the variant is benign. Though c.563A>T has been reported in the literature in individual(s) affected with sporadic CVID (Grimbacher 2006), this report does not provide unequivocal conclusions about association of the variant with CVID. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant for protein expression, ligand binding and signaling function (Fried 2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Immunodeficiency, common variable, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Common Variable Immune Deficiency, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	19
Dann	Benign	0.79
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.88	P;P
Vest4		0.42
MVP		0.78
MPC		0.054
ClinPred		0.061	T
GERP RS		2.4
Varity_R		0.17
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs74811083; hg19: chr17-16843708;