chr17-16940415-G-T

Variant names:

• chr17-16940415-G-T
• rs72553883
• NM_012452.3:c.542C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_012452.3(TNFRSF13B):​c.542C>A​(p.Ala181Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,614,040 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (44 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30 U:1 O:1
• Conservation: PhyloP100: 0.00700
• Publications: 85 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: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 17-16940415-G-T is Pathogenic according to our data. Variant chr17-16940415-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08364344). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00486 (740/152274) while in subpopulation NFE AF = 0.006 (408/68008). AF 95% confidence interval is 0.00552. There are 5 homozygotes in GnomAd4. There are 427 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 5 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.542C>A	p.Ala181Glu	missense	Exon 4 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.542C>A	p.Ala181Glu	missense	Exon 4 of 5	ENSP00000261652.2	O14836-1
	TNFRSF13B	ENST00000583789.1	TSL:1	c.404C>A	p.Ala135Glu	missense	Exon 3 of 4	ENSP00000462952.1	O14836-2
	TNFRSF13B	ENST00000579315.5	TSL:3	c.446-7239C>A		intron	N/A	ENSP00000464069.1	J3QR67

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 740 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00533 AC: 1336 AN: 250718 AF XY: 0.00526

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00544 AC: 7954 AN: 1461766 Hom.: 44 Cov.: 31 AF XY: 0.00532 AC XY: 3867 AN XY: 727176

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0254 AC: 1355 AN: 53340

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5736

European-Non Finnish (NFE) AF: 0.00567 AC: 6310 AN: 1112010

Other (OTH) AF: 0.00344 AC: 208 AN: 60388

GnomAD4 genome AF: 0.00486 AC: 740 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74454

African (AFR) AF: 0.000794 AC: 33 AN: 41568

American (AMR) AF: 0.00190 AC: 29 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00600 AC: 408 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00355 Hom.: 2

Bravo AF: 0.00321

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00534 AC: 648

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	1	-	not provided (13)
11	-	-	Immunodeficiency, common variable, 2 (13)
3	-	-	Immunoglobulin A deficiency 2 (3)
1	-	-	Common variable immunodeficiency (1)
1	-	-	Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.084	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.0070
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.61
Sift	Benign	0.069	T
Sift4G	Benign	0.23	T
Polyphen		0.89	P
Vest4		0.47
MVP		0.87
MPC		0.069
ClinPred		0.057	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.46
Mutation Taster		=90/10	disease causing (ClinVar)

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: rs72553883; hg19: chr17-16843729; COSMIC: COSV108022594; COSMIC: COSV108022594;