1-1203622-G-C

Variant names:

• chr1-1203622-G-C
• ENST00000328596.10:c.737C>G

Variant summary

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

The NM_148901.2(TNFRSF18):​c.737C>G​(p.Ser246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFRSF18 NM_148901.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.431

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=0.19454935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*222C>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.737C>G	p.Ser246Cys	missense_variant	Exon 4 of 4		NP_683699.1
TNFRSF18	XM_017002722.3	c.1013C>G	p.Ser338Cys	missense_variant	Exon 4 of 4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*222C>G		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.737C>G	p.Ser246Cys	missense_variant	Exon 4 of 4	1		ENSP00000328207.6
TNFRSF18	ENST00000379268	c.*222C>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_004195.3	ENSP00000368570.2
TNFRSF18	ENST00000379265.5	c.*222C>G		downstream_gene_variant		1		ENSP00000368567.5
TNFRSF18	ENST00000486728.5	c.*222C>G		downstream_gene_variant		1		ENSP00000462735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381278 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 680890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.737C>G (p.S246C) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a C to G substitution at nucleotide position 737, causing the serine (S) at amino acid position 246 to be replaced by a cysteine (C). 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	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.5
DANN	Benign	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.21		Loss of glycosylation at S246 (P = 0.0032);
MVP		0.23
MPC		0.14
ClinPred		0.99	D
GERP RS		2.7
gMVP		0.079

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: chr1-1139002;