rs56063729

Variant names:

• chr17-16939770-A-G
• rs56063729
• NM_012452.3:c.659T>C

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.659T>C​(p.Val220Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,611,396 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (21 hom., cov: 33)
  • Exomes 𝑓: 0.018 (298 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.29
• Publications: 14 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=0.003712356).
• BP6: Variant 17-16939770-A-G is Benign according to our data. Variant chr17-16939770-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36878.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 = 0.0152 (2321/152312) while in subpopulation NFE AF = 0.0215 (1464/68014). AF 95% confidence interval is 0.0206. There are 21 homozygotes in GnomAd4. There are 1061 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.659T>C	p.Val220Ala	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.659T>C	p.Val220Ala	missense	Exon 5 of 5	ENSP00000261652.2	O14836-1
	TNFRSF13B	ENST00000583789.1	TSL:1	c.521T>C	p.Val174Ala	missense	Exon 4 of 4	ENSP00000462952.1	O14836-2
	TNFRSF13B	ENST00000579315.5	TSL:3	c.446-6594T>C		intron	N/A	ENSP00000464069.1	J3QR67

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2321 AN: 152194 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0162 AC: 3965 AN: 244680 AF XY: 0.0162

Gnomad AFR exome AF: 0.00255

Gnomad AMR exome AF: 0.00839

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0179 AC: 26112 AN: 1459084 Hom.: 298 Cov.: 35 AF XY: 0.0177 AC XY: 12844 AN XY: 725640

African (AFR) AF: 0.00272 AC: 91 AN: 33448

American (AMR) AF: 0.00886 AC: 395 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 929 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00138 AC: 119 AN: 85970

European-Finnish (FIN) AF: 0.0297 AC: 1566 AN: 52734

Middle Eastern (MID) AF: 0.00692 AC: 38 AN: 5488

European-Non Finnish (NFE) AF: 0.0198 AC: 21999 AN: 1110928

Other (OTH) AF: 0.0162 AC: 975 AN: 60242

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152312 Hom.: 21 Cov.: 33 AF XY: 0.0142 AC XY: 1061 AN XY: 74480

African (AFR) AF: 0.00354 AC: 147 AN: 41574

American (AMR) AF: 0.0125 AC: 192 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0292 AC: 310 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1464 AN: 68014

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0202 Hom.: 97

Bravo AF: 0.0134

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0244 AC: 210

ExAC AF: 0.0162 AC: 1963

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Immunodeficiency, common variable, 2 (2)
-	-	1	Common Variable Immune Deficiency, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.0070
DANN	Benign	0.36
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.050	N
REVEL	Uncertain	0.30
Sift	Benign	0.93	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.012
ClinPred		0.0013	T
GERP RS		-6.2
Varity_R		0.016
gMVP		0.072
Mutation Taster		=99/1	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: rs56063729; hg19: chr17-16843084; COSMIC: COSV99077561; COSMIC: COSV99077561;