1-1203610-G-A

Variant names:

Variant summary

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

The NM_148901.2(TNFRSF18):c.749C>T(p.Pro250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,526,560 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TNFRSF18
NM_148901.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

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:

Genome browser will be placed here

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=0.042518646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF18	NM_004195.3 link	c.*234C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000379268.7	NP_004186.1	Q9Y5U5-1
TNFRSF18	NM_148901.2 link	c.749C>T	p.Pro250Leu	missense_variant	Exon 4 of 4		NP_683699.1	Q9Y5U5-2
TNFRSF18	XM_017002722.3 link	c.1025C>T	p.Pro342Leu	missense_variant	Exon 4 of 4		XP_016858211.1	A0A0R7FDM1
TNFRSF18	NM_148902.2 link	c.*234C>T		3_prime_UTR_variant	Exon 5 of 5		NP_683700.1	Q9Y5U5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF18	ENST00000328596.10 link	c.749C>T	p.Pro250Leu	missense_variant	Exon 4 of 4	1		ENSP00000328207.6	Q9Y5U5-2
TNFRSF18	ENST00000379268 link	c.*234C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_004195.3	ENSP00000368570.2	Q9Y5U5-1
TNFRSF18	ENST00000379265.5 link	c.*234C>T		downstream_gene_variant		1		ENSP00000368567.5	Q9Y5U5-3
TNFRSF18	ENST00000486728.5 link	c.*234C>T		downstream_gene_variant		1		ENSP00000462735.1	J3KT02

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000571

AC:

AN:

175280

Hom.:

AF XY:

0.00

AC XY:

AN XY:

95028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000626

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1374360

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000838

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.749C>T (p.P250L) 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 749, causing the proline (P) at amino acid position 250 to be replaced by a leucine (L). 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

-0.49

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.7

DANN

Benign

0.54

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.34

M_CAP

Benign

0.024

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.42

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.12

Vest4

0.13

MutPred

0.070

Loss of glycosylation at S255 (P = 0.0605);

MVP

0.28

MPC

0.022

ClinPred

0.047

GERP RS

1.4

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

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