1-1203655-C-G

Variant names:

• chr1-1203655-C-G
• ENST00000328596.10:c.704G>C

Variant summary

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

The NM_148901.2(TNFRSF18):​c.704G>C​(p.Arg235Thr) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF18 NM_148901.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.356

Genes affected

TNFRSF18 (HGNC:11914): (TNF receptor superfamily member 18) This gene encodes a member of the TNF-receptor superfamily. The encoded receptor has been shown to have increased expression upon T-cell activation, and it is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. Knockout studies in mice also suggest the role of this receptor is in the regulation of CD3-driven T-cell activation and programmed cell death. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Feb 2011]

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=0.09052259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*189G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.704G>C	p.Arg235Thr	missense_variant	Exon 4 of 4		NP_683699.1
TNFRSF18	XM_017002722.3	c.980G>C	p.Arg327Thr	missense_variant	Exon 4 of 4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*189G>C		3_prime_UTR_variant	Exon 5 of 5		NP_683700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000328596.10	c.704G>C	p.Arg235Thr	missense_variant	Exon 4 of 4	1		ENSP00000328207.6
TNFRSF18	ENST00000379268	c.*189G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_004195.3	ENSP00000368570.2
TNFRSF18	ENST00000379265.5	c.*189G>C		downstream_gene_variant		1		ENSP00000368567.5
TNFRSF18	ENST00000486728.5	c.*189G>C		downstream_gene_variant		1		ENSP00000462735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.704G>C (p.R235T) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a G to C substitution at nucleotide position 704, causing the arginine (R) at amino acid position 235 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.6
DANN	Benign	0.58
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.097
Sift	Benign	0.33	T
Sift4G	Benign	0.23	T
Polyphen		0.42	B
Vest4		0.26
MutPred		0.15		Gain of phosphorylation at R235 (P = 0.0081);
MVP		0.31
MPC		0.027
ClinPred		0.15	T
GERP RS		2.7
gMVP		0.15

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: chr1-1139035;