17-16939448-T-TC

Variant names:

• chr17-16939448-T-TC
• rs555681458
• NM_012452.3:c.*98dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_012452.3(TNFRSF13B):​c.*98dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,380,772 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: TNFRSF13B NM_012452.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.951

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]

ENSG00000307457 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-16939448-T-TC is Benign according to our data. Variant chr17-16939448-T-TC is described in ClinVar as [Benign]. Clinvar id is 933200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00187 (282/150434) while in subpopulation AFR AF = 0.00651 (267/41036). AF 95% confidence interval is 0.00587. There are 1 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3	c.*98dupG		3_prime_UTR_variant	Exon 5 of 5	ENST00000261652.7	NP_036584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.*98dupG		3_prime_UTR_variant	Exon 5 of 5	1	NM_012452.3	ENSP00000261652.2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 282 AN: 150316 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.000971

GnomAD4 exome AF: 0.000198 AC: 243 AN: 1230338 Hom.: 2 Cov.: 18 AF XY: 0.000150 AC XY: 90 AN XY: 601824

African (AFR) AF: 0.00700 AC: 198 AN: 28270

American (AMR) AF: 0.000163 AC: 5 AN: 30646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20892

East Asian (EAS) AF: 0.00 AC: 0 AN: 34010

South Asian (SAS) AF: 0.0000301 AC: 2 AN: 66362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.0000251 AC: 24 AN: 955168

Other (OTH) AF: 0.000269 AC: 14 AN: 52084

GnomAD4 genome AF: 0.00187 AC: 282 AN: 150434 Hom.: 1 Cov.: 30 AF XY: 0.00189 AC XY: 139 AN XY: 73410

African (AFR) AF: 0.00651 AC: 267 AN: 41036

American (AMR) AF: 0.000662 AC: 10 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 4848

South Asian (SAS) AF: 0.00 AC: 0 AN: 4650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67564

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00249

Asia WGS AF: 0.000581 AC: 2 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 25, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF13B c.*98dupG is located in the untranslated mRNA region downstream of the termination codon. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 30888 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 691 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*98dupG in individuals affected with Common Variable Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism

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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Other links and lift over

dbSNP: rs555681458; hg19: chr17-16842762;