1-7933173-A-G

Position:

• chr1-7933173-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001561.6(TNFRSF9):​c.668T>C​(p.Ile223Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF9 NM_001561.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

TNFRSF9 (HGNC:11924): (TNF receptor superfamily member 9) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1215682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF9	NM_001561.6	c.668T>C	p.Ile223Thr	missense_variant	7/8	ENST00000377507.8	NP_001552.2
TNFRSF9	XM_006710618.4	c.668T>C	p.Ile223Thr	missense_variant	7/8		XP_006710681.1
TNFRSF9	XM_047419672.1	c.668T>C	p.Ile223Thr	missense_variant	7/8		XP_047275628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.668T>C	p.Ile223Thr	missense_variant	7/8	1	NM_001561.6	ENSP00000366729.3
TNFRSF9	ENST00000474475.1	c.212T>C	p.Ile71Thr	missense_variant	2/3	3		ENSP00000465272.1
TNFRSF9	ENST00000492571.1	n.*310T>C		non_coding_transcript_exon_variant	5/5	3		ENSP00000464978.1
TNFRSF9	ENST00000492571.1	n.*310T>C		3_prime_UTR_variant	5/5	3		ENSP00000464978.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TNFRSF9 protein (p.Ile223Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNFRSF9-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.70	T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	.;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.014	.;D;.
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.14	B;B;.
Vest4		0.29
MutPred		0.43		Loss of stability (P = 0.0022);Loss of stability (P = 0.0022);.;
MVP		0.44
MPC		0.12
ClinPred		0.37	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs1639759465; hg19: chr1-7993233;