rs2298213

Positions:

• chr1-1203822-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_148901.2(TNFRSF18):​c.537A>G​(p.Pro179Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0832 in 1,582,584 control chromosomes in the GnomAD database, including 11,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (4217 hom., cov: 33)
  • Exomes 𝑓: 0.074 (6962 hom.)
• Consequence: TNFRSF18 NM_148901.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP7: Synonymous conserved (PhyloP=-0.363 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*22A>G		3_prime_UTR_variant	5/5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.537A>G	p.Pro179Pro	synonymous_variant	4/4		NP_683699.1
TNFRSF18	XM_017002722.3	c.813A>G	p.Pro271Pro	synonymous_variant	4/4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*22A>G		3_prime_UTR_variant	5/5		NP_683700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000328596.10	c.537A>G	p.Pro179Pro	synonymous_variant	4/4	1		ENSP00000328207.6
TNFRSF18	ENST00000379268	c.*22A>G		3_prime_UTR_variant	5/5	1	NM_004195.3	ENSP00000368570.2
TNFRSF18	ENST00000379265.5	c.*22A>G		downstream_gene_variant		1		ENSP00000368567.5
TNFRSF18	ENST00000486728.5	c.*22A>G		downstream_gene_variant		1		ENSP00000462735.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25608 AN: 152044 Hom.: 4186 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.0905 AC: 17978 AN: 198568 Hom.: 1605 AF XY: 0.0841 AC XY: 9231 AN XY: 109726

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.0729

Gnomad ASJ exome AF: 0.0856

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.0670

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0579

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.0741 AC: 105961 AN: 1430422 Hom.: 6962 Cov.: 33 AF XY: 0.0725 AC XY: 51518 AN XY: 710548

Gnomad4 AFR exome AF: 0.458

Gnomad4 AMR exome AF: 0.0755

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.0677

Gnomad4 FIN exome AF: 0.0661

Gnomad4 NFE exome AF: 0.0588

Gnomad4 OTH exome AF: 0.0994

GnomAD4 genome AF: 0.169 AC: 25699 AN: 152162 Hom.: 4217 Cov.: 33 AF XY: 0.166 AC XY: 12317 AN XY: 74390

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.0948

Gnomad4 ASJ AF: 0.0937

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0712

Gnomad4 FIN AF: 0.0568

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.143

Alfa AF: 0.0901 Hom.: 419

Bravo AF: 0.184

Asia WGS AF: 0.144 AC: 500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.2
DANN	Benign	0.37

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: rs2298213; hg19: chr1-1139202; COSMIC: COSV60775814; COSMIC: COSV60775814;