1-1203940-C-T

Position:

chr1-1203940-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_148901.2(TNFRSF18):c.419G>A(p.Arg140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,607,266 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TNFRSF18
NM_148901.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.48

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015988618).

BP6

Variant 1-1203940-C-T is Benign according to our data. Variant chr1-1203940-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2343651.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF18	NM_004195.3 link	c.630G>A	p.Pro210Pro	synonymous_variant	5/5	ENST00000379268.7	NP_004186.1	Q9Y5U5-1
TNFRSF18	NM_148901.2 link	c.419G>A	p.Arg140His	missense_variant	4/4		NP_683699.1	Q9Y5U5-2
TNFRSF18	XM_017002722.3 link	c.695G>A	p.Arg232His	missense_variant	4/4		XP_016858211.1	A0A0R7FDM1
TNFRSF18	NM_148902.2 link	c.609G>A	p.Pro203Pro	synonymous_variant	5/5		NP_683700.1	Q9Y5U5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNFRSF18	ENST00000328596.10 link	c.419G>A	p.Arg140His	missense_variant	4/4	1		ENSP00000328207.6	Q9Y5U5-2
TNFRSF18	ENST00000379268.7 link	c.630G>A	p.Pro210Pro	synonymous_variant	5/5	1	NM_004195.3	ENSP00000368570.2	Q9Y5U5-1
TNFRSF18	ENST00000379265.5 link	c.609G>A	p.Pro203Pro	synonymous_variant	5/5	1		ENSP00000368567.5	Q9Y5U5-3
TNFRSF18	ENST00000486728.5 link	c.414G>A	p.Pro138Pro	synonymous_variant	4/4	1		ENSP00000462735.1	J3KT02

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000311

AC:

AN:

234524

Hom.:

AF XY:

0.000286

AC XY:

AN XY:

129178

show subpopulations

Gnomad AFR exome

AF:

0.000208

Gnomad AMR exome

AF:

0.000469

Gnomad ASJ exome

AF:

0.000416

Gnomad EAS exome

AF:

0.000225

Gnomad SAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000864

GnomAD4 exome

AF:

0.000239

AC:

347

AN:

1454896

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

185

AN XY:

723822

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000538

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.000125

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000171

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000224

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000358

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.6

DANN

Uncertain

0.99

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.39

M_CAP

Benign

0.0023

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.43

REVEL

Benign

0.029

Sift

Pathogenic

0.0

Sift4G

Benign

0.21

Polyphen

0.0020

Vest4

0.092

MVP

0.061

MPC

0.086

ClinPred

0.028

GERP RS

-4.3

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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