17-16940415-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_012452.3(TNFRSF13B):​c.542C>G​(p.Ala181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. A181E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF13B NM_012452.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• 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

ENSG00000307457 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-16940415-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=0.22614035).

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.542C>G	p.Ala181Gly	missense	Exon 4 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.542C>G	p.Ala181Gly	missense	Exon 4 of 5	ENSP00000261652.2
	TNFRSF13B	ENST00000583789.1	TSL:1	c.404C>G	p.Ala135Gly	missense	Exon 3 of 4	ENSP00000462952.1
	TNFRSF13B	ENST00000579009.1	TSL:6	n.648C>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	6.9
DANN	Benign	0.75
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.0070
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D
Sift4G	Benign	0.38	T
Polyphen		0.70	P
Vest4		0.23
MutPred		0.41		Loss of stability (P = 0.189)
MVP		0.79
MPC		0.055
ClinPred		0.33	T
GERP RS		2.4
Varity_R		0.089
gMVP		0.21

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;