17-16948968-C-T

Variant names:

• chr17-16948968-C-T
• rs55916807
• NM_012452.3:c.215G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012452.3(TNFRSF13B):​c.215G>A​(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,006 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.12
• Publications: 12 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), Laboratory for Molecular Medicine, ClinGen, G2P, Ambry Genetics
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008713514).
• BP6: Variant 17-16948968-C-T is Benign according to our data. Variant chr17-16948968-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 322027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00257 (391/152164) while in subpopulation NFE AF = 0.00462 (314/68012). AF 95% confidence interval is 0.0042. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	NM_012452.3	MANE Select	c.215G>A	p.Arg72His	missense	Exon 3 of 5	NP_036584.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF13B	ENST00000261652.7	TSL:1 MANE Select	c.215G>A	p.Arg72His	missense	Exon 3 of 5	ENSP00000261652.2
	TNFRSF13B	ENST00000583789.1	TSL:1	c.77G>A	p.Arg26His	missense	Exon 2 of 4	ENSP00000462952.1
	TNFRSF13B	ENST00000579315.5	TSL:3	c.215G>A	p.Arg72His	missense	Exon 3 of 4	ENSP00000464069.1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 152046 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00202 AC: 507 AN: 251186 AF XY: 0.00185

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00368 AC: 5376 AN: 1461842 Hom.: 13 Cov.: 35 AF XY: 0.00346 AC XY: 2519 AN XY: 727220

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00210 AC: 94 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86248

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00450 AC: 5003 AN: 1112000

Other (OTH) AF: 0.00328 AC: 198 AN: 60394

GnomAD4 genome AF: 0.00257 AC: 391 AN: 152164 Hom.: 2 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74386

African (AFR) AF: 0.000699 AC: 29 AN: 41506

American (AMR) AF: 0.00249 AC: 38 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00330 Hom.: 4

Bravo AF: 0.00251

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00172 AC: 209

EpiCase AF: 0.00327

EpiControl AF: 0.00320

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	1	Common Variable Immune Deficiency, Dominant (1)
-	-	1	Immunodeficiency, common variable, 2 (1)
-	-	1	Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Benign	0.63
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0087	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.11	N
PhyloP100		-1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.090	N
REVEL	Uncertain	0.50
Sift	Benign	0.31	T
Sift4G	Benign	0.22	T
Polyphen		0.0030	B
Vest4		0.19
MVP		0.32
MPC		0.013
ClinPred		0.0068	T
GERP RS		-9.9
Varity_R		0.054
gMVP		0.19
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55916807; hg19: chr17-16852282;