chr17-16948923-A-G

Variant names:

• chr17-16948923-A-G
• rs72553877
• NM_012452.3:c.260T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_012452.3(TNFRSF13B):​c.260T>C​(p.Ile87Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I87N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-16948923-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 618436.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

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.260T>C	p.Ile87Thr	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.260T>C	p.Ile87Thr	missense	Exon 3 of 5	ENSP00000261652.2
	TNFRSF13B	ENST00000583789.1	TSL:1	c.122T>C	p.Ile41Thr	missense	Exon 2 of 4	ENSP00000462952.1
	TNFRSF13B	ENST00000579315.5	TSL:3	c.260T>C	p.Ile87Thr	missense	Exon 3 of 4	ENSP00000464069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.75
MutPred		0.61		Loss of stability (P = 0.0389)
MVP		0.89
MPC		0.046
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.37

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: rs72553877; hg19: chr17-16852237;