chr17-16948923-A-T

Variant names:

• chr17-16948923-A-T
• rs72553877
• NM_012452.3:c.260T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3 PP5 BS1_Supporting

The NM_012452.3(TNFRSF13B):​c.260T>A​(p.Ile87Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000478 in 1,614,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:3 O:1
• Conservation: PhyloP100: 4.18

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 17-16948923-A-T is Pathogenic according to our data. Variant chr17-16948923-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618436.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3, Pathogenic=2, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000491 (718/1461876) while in subpopulation NFE AF= 0.000578 (643/1111996). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4_exome. There are 355 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3	c.260T>A	p.Ile87Asn	missense_variant	Exon 3 of 5	ENST00000261652.7	NP_036584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.260T>A	p.Ile87Asn	missense_variant	Exon 3 of 5	1	NM_012452.3	ENSP00000261652.2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000457 AC: 115 AN: 251460 Hom.: 0 AF XY: 0.000449 AC XY: 61 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000491 AC: 718 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.000488 AC XY: 355 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000578

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74500

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000662 Hom.: 1

Bravo AF: 0.000423

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 2 Pathogenic:5 Uncertain:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 2 (MIM#240500) and immunoglobulin A deficiency 2 (MIM#609529). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with monoallelic or biallelic variants have been reported (PMIDs: 34210994, 34441032). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 34210994). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (771 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TACI, cysteine-rich domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported three times as pathogenic, three times as likely pathogenic and twice as a VUS (ClinVar). It has also been reported in multiple individuals with common variable immunodeficiency in the literature in both the heterozygous and compound heterozygous state, however has also been reported in many unaffected heterozygous individuals (PMIDs: 22884984, 18981294, 22627058, 37678716, 27123465, 34441032, 33838017). (I) 0906 - Segregation evidence for this variant is inconclusive. There are conflicting reports of individuals inheriting this variant from an affected parent (PMID: 18981294) as well as from unaffected parents (PMID: 37678716). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cells expressing this variant demonstrated partially reduced ligand binding and impaired NFAT signalling when compared to wildtype cells (PMIDs: 21419480, 22627058). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 19, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.043%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 0.87). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000618436 /PMID: 18981294). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 18, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PS3_MOD -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 87 of the TNFRSF13B protein (p.Ile87Asn). This variant is present in population databases (rs72553877, gnomAD 0.07%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 22627058, 22697072, 22884984, 27123465, 30290665, 31681265). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 618436). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF13B protein function. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 21419480, 21458042). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2 Uncertain:2

Mar 19, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile87Asn variant (rs72553877) has been reported in the heterozygous and compound heterozygous state in multiple families and individuals diagnosed with common variable immunodeficiency (CVID), asthma, or lymphoproliferative disorders (Freiberger 2012, Janzi 2012, Lougaris 2012, Salzer 2009, and Speletas 2013). This variant has also been observed by our laboratory in a patient who inherited the variant from his unaffected father and was reported to have chronic infections and IgA deficiency. Functional evidence demonstrates that the p.Ile87Asn variant causes a defect in ligand binding as well as reduced activation of NFkB signaling (Fried 2011, Lougaris 2012, and Salzer 2009). The p.Ile87Asn variant is also listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.068% in the non-Finnish European population (identified in 86 out of 126,692 chromosomes), but was not detected in the homozygous state. The isoleucine at codon 87 is moderately conserved considering 10 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the TNFRSF13B protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Therefore, based on the available evidence, the p.Ile87Asn variant is classified as likely pathogenic. -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF13B: PS4:Moderate, PP1, PS3:Supporting -

Feb 18, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a single heterozygous variant in patients with common variable immune deficiency or selective IgA deficiency in the published literature, as well as in unaffected individuals (PMID: 22697072, 22930256, 27123465); Published functional studies demonstrate no effect on cell surface expression, but a significant reduction in signaling (PMID: 21419480); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21041728, 34975878, 23956760, 17697196, 18981294, 21850030, 22884984, 22627058, 19494827, 21458042, 19629655, 28554560, 22930256, 27123465, 30269248, 30290665, 31681265, 34426522, 31589614, 35686370, 34573280, 32581362, 34441032, 37678716, 37652172, 22697072, 21419480, 38282561, 39006921, 39726076, 39873967) -

Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Pathogenic:1

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Common variable immunodeficiency Pathogenic:1

Jul 10, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNFRSF13B c.260T>A (p.Ile87Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 254886 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (0.00046 vs 0.0024), allowing no conclusion about variant significance. c.260T>A has been reported in heterozygous and presumed compound heterozygous state in individuals affected with Common Variable Immunodeficiency (e.g. Bacchelli_2007, Pan-Hammarstrom_2008, PanSalzer_2009, Lougaris_2012, Rojas-Restrepo_2021, Fioredda_2022, Peng_2023, Salih_2023). In some families the variant has been inherited from an unaffected parent and authors described this allele as a risk allele (Peng_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant resulted in decreased activity (Salzer_2009, Fried_2011, Lougaris_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18978466, 19629655, 17697196, 21419480, 21850030, 22627058, 18200502, 34975878, 18981294, 37678716, 37652172, 35686370). ClinVar contains an entry for this variant (Variation ID: 618436). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

IgAD1;C3150354:Immunodeficiency, common variable, 2 Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 06-12-2021 by Lab or GTR ID 26957. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Benign	0.66
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.1	.;D;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99, 0.98	.;D;D
Vest4		0.86
MVP		0.85
MPC		0.077
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.82
gMVP		0.51

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: rs72553877; hg19: chr17-16852237;