17-16939598-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012452.3(TNFRSF13B):c.831T>C(p.Ser277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,612,726 control chromosomes in the GnomAD database, including 168,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19706 hom., cov: 31)
  • Exomes 𝑓: 0.44 (149108 hom.)
• Consequence: TNFRSF13B NM_012452.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.875

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-16939598-A-G is Benign according to our data. Variant chr17-16939598-A-G is described in ClinVar as [Benign]. Clinvar id is 260259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-16939598-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.875 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.831T>C	p.Ser277=	synonymous_variant	5/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.831T>C	p.Ser277=	synonymous_variant	5/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75120 AN: 151718 Hom.: 19662 Cov.: 31

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.495 AC: 122856 AN: 248314 Hom.: 32451 AF XY: 0.492 AC XY: 66151 AN XY: 134406

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.798

Gnomad SAS exome AF: 0.615

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.442 AC: 645265 AN: 1460890 Hom.: 149108 Cov.: 52 AF XY: 0.446 AC XY: 324418 AN XY: 726644

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.559

Gnomad4 ASJ exome AF: 0.453

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.611

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.495 AC: 75222 AN: 151836 Hom.: 19706 Cov.: 31 AF XY: 0.499 AC XY: 36977 AN XY: 74172

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.810

Gnomad4 SAS AF: 0.610

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.466

Alfa AF: 0.435 Hom.: 17351

Bravo AF: 0.514

Asia WGS AF: 0.708 AC: 2461 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.417

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Immunodeficiency, common variable, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 04, 2019	- -

Common Variable Immune Deficiency, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.53
Dann	Benign	0.37

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: rs11078355; hg19: chr17-16842912; COSMIC: COSV55425240; COSMIC: COSV55425240;