rs56063729

chr17-16939770-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012452.3(TNFRSF13B):c.659T>C(p.Val220Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,611,396 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (21 hom., cov: 33)
  • Exomes 𝑓: 0.018 (298 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.29

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=0.003712356).
• BP6: Variant 17-16939770-A-G is Benign according to our data. Variant chr17-16939770-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 36878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-16939770-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2321/152312) while in subpopulation NFE AF= 0.0215 (1464/68014). AF 95% confidence interval is 0.0206. There are 21 homozygotes in gnomad4. There are 1061 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF13B	NM_012452.3	c.659T>C	p.Val220Ala	missense_variant	5/5	ENST00000261652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.659T>C	p.Val220Ala	missense_variant	5/5	1	NM_012452.3	P2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2321 AN: 152194 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0162 AC: 3965 AN: 244680 Hom.: 56 AF XY: 0.0162 AC XY: 2153 AN XY: 133122

Gnomad AFR exome AF: 0.00255

Gnomad AMR exome AF: 0.00839

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0179 AC: 26112 AN: 1459084 Hom.: 298 Cov.: 35 AF XY: 0.0177 AC XY: 12844 AN XY: 725640

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00886

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152312 Hom.: 21 Cov.: 33 AF XY: 0.0142 AC XY: 1061 AN XY: 74480

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0211 Hom.: 55

Bravo AF: 0.0134

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0244 AC: 210

ExAC AF: 0.0162 AC: 1963

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Immunodeficiency, common variable, 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Common Variable Immune Deficiency, Dominant Benign:1

Likely 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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.0070
Dann	Benign	0.36
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.050	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.93	T;.
Sift4G	Benign	0.75	T;T
Polyphen		0.0	B;B
Vest4		0.013
MPC		0.012
ClinPred		0.0013	T
GERP RS		-6.2
Varity_R		0.016
gMVP		0.072

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: rs56063729; hg19: chr17-16843084; COSMIC: COSV99077561; COSMIC: COSV99077561;