17-16940415-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PS1_Moderate PM1 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. 14/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_012452.3 (TNFRSF13B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical; Signal-anchor for type III membrane protein (size 20) in uniprot entity TR13B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_012452.3
• 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 Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.22614035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF13B	NM_012452.3	c.542C>G	p.Ala181Gly	missense_variant	Exon 4 of 5	ENST00000261652.7	NP_036584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF13B	ENST00000261652.7	c.542C>G	p.Ala181Gly	missense_variant	Exon 4 of 5	1	NM_012452.3	ENSP00000261652.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D;.
Sift4G	Benign	0.38	T;T
Polyphen		0.70	P;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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-16843729;