Variant 1-1203701-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_148901.2(TNFRSF18):c.658C>T(p.Arg220Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

TNFRSF18
NM_148901.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Variant links:

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]

TNFRSF18 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03449732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF18	NM_004195.3 link	c.*143C>T		3_prime_UTR_variant	5/5	ENST00000379268.7	NP_004186.1	Q9Y5U5-1
TNFRSF18	NM_148901.2 link	c.658C>T	p.Arg220Cys	missense_variant	4/4		NP_683699.1	Q9Y5U5-2
TNFRSF18	XM_017002722.3 link	c.934C>T	p.Arg312Cys	missense_variant	4/4		XP_016858211.1	A0A0R7FDM1
TNFRSF18	NM_148902.2 link	c.*143C>T		3_prime_UTR_variant	5/5		NP_683700.1	Q9Y5U5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000328596.10 link	c.658C>T	p.Arg220Cys	missense_variant	4/4	1		ENSP00000328207.6		Q9Y5U5-2
TNFRSF18	ENST00000379268 link	c.*143C>T		3_prime_UTR_variant	5/5	1	NM_004195.3	ENSP00000368570.2		Q9Y5U5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181884

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

99272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000424

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1410138

Hom.:

Cov.:

AF XY:

0.00000573

AC XY:

AN XY:

697964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000366

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000836

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.658C>T (p.R220C) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a C to T substitution at nucleotide position 658, causing the arginine (R) at amino acid position 220 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

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.1

DANN

Benign

0.96

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.47

M_CAP

Benign

0.0056

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.050

Polyphen

0.0010

Vest4

0.13

MutPred

0.19

Loss of MoRF binding (P = 0.0495);

MVP

0.040

MPC

0.058

ClinPred

0.071

GERP RS

-3.3

gMVP

0.097

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over