1-1203668-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_148901.2(TNFRSF18):​c.691G>A​(p.Gly231Arg) 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. 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: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TNFRSF18
NM_148901.2 missense

Scores

2
1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0970
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.09523308).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNFRSF18NM_004195.3 linkc.*176G>A 3_prime_UTR_variant Exon 5 of 5 ENST00000379268.7 NP_004186.1 Q9Y5U5-1
TNFRSF18NM_148901.2 linkc.691G>A p.Gly231Arg missense_variant Exon 4 of 4 NP_683699.1 Q9Y5U5-2
TNFRSF18XM_017002722.3 linkc.967G>A p.Gly323Arg missense_variant Exon 4 of 4 XP_016858211.1 A0A0R7FDM1
TNFRSF18NM_148902.2 linkc.*176G>A 3_prime_UTR_variant Exon 5 of 5 NP_683700.1 Q9Y5U5-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFRSF18ENST00000328596.10 linkc.691G>A p.Gly231Arg missense_variant Exon 4 of 4 1 ENSP00000328207.6 Q9Y5U5-2
TNFRSF18ENST00000379268 linkc.*176G>A 3_prime_UTR_variant Exon 5 of 5 1 NM_004195.3 ENSP00000368570.2 Q9Y5U5-1
TNFRSF18ENST00000379265.5 linkc.*176G>A downstream_gene_variant 1 ENSP00000368567.5 Q9Y5U5-3
TNFRSF18ENST00000486728.5 linkc.*176G>A downstream_gene_variant 1 ENSP00000462735.1 J3KT02

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1396876
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
690102
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.691G>A (p.G231R) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a G to A substitution at nucleotide position 691, causing the glycine (G) at amino acid position 231 to be replaced by an arginine (R). 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
-0.30
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
2.9
DANN
Uncertain
0.99
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.42
T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.095
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.28
N
REVEL
Benign
0.032
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.39
B
Vest4
0.26
MutPred
0.11
Gain of MoRF binding (P = 0.0202);
MVP
0.21
MPC
0.19
ClinPred
0.53
D
GERP RS
1.6
gMVP
0.19

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.

Other links and lift over

dbSNP: rs756063874; hg19: chr1-1139048; COSMIC: COSV100148920; COSMIC: COSV100148920; API