19-6534952-C-G

Variant names:

• chr19-6534952-C-G
• NM_003811.4:c.651C>G
• TNFSF9 p.His217Gln

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003811.4(TNFSF9):​c.651C>G​(p.His217Gln) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TNFSF9 NM_003811.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331
• Publications: 0 publications found

Genes affected

TNFSF9 (HGNC:11939): (TNF superfamily member 9) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.[provided by RefSeq, Oct 2008]

TNFSF9 Gene-Disease associations (from GenCC):

• hereditary predisposition to infections

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1713649).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003811.4. 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
	TNFSF9	NM_003811.4	MANE Select	c.651C>G	p.His217Gln	missense	Exon 3 of 3	NP_003802.1	P41273

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF9	ENST00000245817.5	TSL:1 MANE Select	c.651C>G	p.His217Gln	missense	Exon 3 of 3	ENSP00000245817.2	P41273

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.12
DANN	Benign	0.63
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.33
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.20
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-6534963;