rs34557412

Variant names:

• chr17-16948873-A-G
• rs34557412
• NM_012452.3:c.310T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-16948873-A-G
• chr17-16948873-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM5 PP5 BP4 BS1_Supporting BS2

The NM_012452.3(TNFRSF13B):​c.310T>C​(p.Cys104Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00544 in 1,614,226 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C104Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (28 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:40 U:5 B:1 O:2
• Conservation: PhyloP100: 4.18
• Publications: 154 publications found

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]

TNFRSF13B Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-16948872-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 645207.
• PP5: Variant 17-16948873-A-G is Pathogenic according to our data. Variant chr17-16948873-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 5302.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23062569). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00392 (597/152334) while in subpopulation AMR AF = 0.00713 (109/15298). AF 95% confidence interval is 0.00604. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012452.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	NM_012452.3	MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	NP_036584.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.310T>C	p.Cys104Arg	missense	Exon 3 of 5	ENSP00000261652.2
	TNFRSF13B	ENST00000583789.1	TSL:1	c.172T>C	p.Cys58Arg	missense	Exon 2 of 4	ENSP00000462952.1
	TNFRSF13B	ENST00000579315.5	TSL:3	c.310T>C	p.Cys104Arg	missense	Exon 3 of 4	ENSP00000464069.1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00350 AC: 879 AN: 251490 AF XY: 0.00343

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00560 AC: 8186 AN: 1461892 Hom.: 28 Cov.: 35 AF XY: 0.00533 AC XY: 3875 AN XY: 727246

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00416 AC: 186 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86258

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00675 AC: 7506 AN: 1112010

Other (OTH) AF: 0.00477 AC: 288 AN: 60396

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74502

African (AFR) AF: 0.00147 AC: 61 AN: 41584

American (AMR) AF: 0.00713 AC: 109 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00579 AC: 394 AN: 68018

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00485 Hom.: 2

Bravo AF: 0.00422

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00321 AC: 390

EpiCase AF: 0.00627

EpiControl AF: 0.00605

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
18	2	-	Immunodeficiency, common variable, 2 (22)
13	2	1	not provided (16)
2	-	-	TNFRSF13B-related disorder (2)
1	-	-	Common variable immunodeficiency (1)
1	-	-	Immune deficiency, familial variable (1)
1	-	-	Immunodeficiency, common variable, 1 (1)
1	-	-	Immunoglobulin A deficiency 2 (1)
1	-	-	Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 (1)
-	1	-	not specified (1)
1	-	-	Severe SARS-CoV-2 infection, susceptibility to (1)
-	-	-	Immunodeficiency, common variable, 1;C3150354:Immunodeficiency, common variable, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	26
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.89
MPC		0.084
ClinPred		0.051	T
GERP RS		5.0
Varity_R		0.96
gMVP		0.67
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs34557412; hg19: chr17-16852187; COSMIC: COSV55430181;