rs34562254

Variant names:

• chr17-16939677-G-A
• rs34562254
• NM_012452.3:c.752C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012452.3(TNFRSF13B):​c.752C>T​(p.Pro251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,610,656 control chromosomes in the GnomAD database, including 13,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1409 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11783 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.825
• Publications: 63 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: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P, ClinGen
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307457 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022192597).
• BP6: Variant 17-16939677-G-A is Benign according to our data. Variant chr17-16939677-G-A is described in ClinVar as Benign. ClinVar VariationId is 322025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

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.752C>T	p.Pro251Leu	missense	Exon 5 of 5	NP_036584.1	O14836-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.752C>T	p.Pro251Leu	missense	Exon 5 of 5	ENSP00000261652.2	O14836-1
	TNFRSF13B	ENST00000583789.1	TSL:1	c.614C>T	p.Pro205Leu	missense	Exon 4 of 4	ENSP00000462952.1	O14836-2
	TNFRSF13B	ENST00000579315.5	TSL:3	c.446-6501C>T		intron	N/A	ENSP00000464069.1	J3QR67

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19408 AN: 152080 Hom.: 1411 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.139 AC: 34438 AN: 248042 AF XY: 0.140

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.406

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.115 AC: 168414 AN: 1458458 Hom.: 11783 Cov.: 37 AF XY: 0.117 AC XY: 85143 AN XY: 724934

African (AFR) AF: 0.135 AC: 4501 AN: 33430

American (AMR) AF: 0.103 AC: 4565 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3610 AN: 26014

East Asian (EAS) AF: 0.382 AC: 15145 AN: 39618

South Asian (SAS) AF: 0.160 AC: 13723 AN: 85928

European-Finnish (FIN) AF: 0.0972 AC: 5184 AN: 53306

Middle Eastern (MID) AF: 0.127 AC: 728 AN: 5752

European-Non Finnish (NFE) AF: 0.102 AC: 113099 AN: 1109646

Other (OTH) AF: 0.130 AC: 7859 AN: 60236

GnomAD4 genome AF: 0.128 AC: 19407 AN: 152198 Hom.: 1409 Cov.: 33 AF XY: 0.130 AC XY: 9708 AN XY: 74408

African (AFR) AF: 0.134 AC: 5562 AN: 41526

American (AMR) AF: 0.122 AC: 1860 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.403 AC: 2075 AN: 5150

South Asian (SAS) AF: 0.156 AC: 754 AN: 4822

European-Finnish (FIN) AF: 0.0987 AC: 1047 AN: 10608

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7179 AN: 67998

Other (OTH) AF: 0.111 AC: 235 AN: 2116

Alfa AF: 0.122 Hom.: 2741

Bravo AF: 0.129

TwinsUK AF: 0.104 AC: 384

ALSPAC AF: 0.0981 AC: 378

ESP6500AA AF: 0.134 AC: 589

ESP6500EA AF: 0.110 AC: 945

ExAC AF: 0.139 AC: 16847

Asia WGS AF: 0.249 AC: 867 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Common Variable Immune Deficiency, Dominant (1)
-	-	1	Immunodeficiency, common variable, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.82
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.73	P
Vest4		0.049
MPC		0.013
ClinPred		0.015	T
GERP RS		0.88
Varity_R		0.022
gMVP		0.074
Mutation Taster		=100/0	polymorphism (auto)

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: rs34562254; hg19: chr17-16842991; COSMIC: COSV55425401; COSMIC: COSV55425401;