1-1204417-T-G

Position:

chr1-1204417-T-G

Variant summary

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

The NM_004195.3(TNFRSF18):c.380A>C(p.His127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,498,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TNFRSF18
NM_004195.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -6.57

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 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=0.12782866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFRSF18	NM_004195.3 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/4		NP_683699.1
TNFRSF18	NM_148902.2 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/5		NP_683700.1
TNFRSF18	XM_017002722.3 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/4		XP_016858211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000379268.7 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/5	1	NM_004195.3	ENSP00000368570	A2	Q9Y5U5-1
TNFRSF18	ENST00000328596.10 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/4	1		ENSP00000328207		Q9Y5U5-2
TNFRSF18	ENST00000379265.5 linkuse as main transcript	c.380A>C	p.His127Pro	missense_variant	3/5	1		ENSP00000368567	P2	Q9Y5U5-3
TNFRSF18	ENST00000486728.5 linkuse as main transcript	c.164A>C	p.His55Pro	missense_variant	2/4	1		ENSP00000462735	A2

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145478

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000455

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249722

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135580

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1352710

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

672012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000422

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145478

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70760

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000455

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000403

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

May 20, 2024

The c.380A>C (p.H127P) alteration is located in exon 3 (coding exon 3) of the TNFRSF18 gene. This alteration results from a A to C substitution at nucleotide position 380, causing the histidine (H) at amino acid position 127 to be replaced by a proline (P). 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

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.6

DANN

Benign

0.59

DEOGEN2

Benign

0.12

.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.48

N;N;.;N

MutationTaster

Benign

0.85

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.8

D;N;.;N

REVEL

Benign

0.26

Sift

Uncertain

0.016

D;T;.;T

Sift4G

Uncertain

0.023

D;T;T;T

Polyphen

0.98

D;P;.;.

Vest4

0.17

MutPred

0.30

Gain of disorder (P = 0.0946);Gain of disorder (P = 0.0946);.;Gain of disorder (P = 0.0946);

MVP

0.35

MPC

0.11

ClinPred

0.26

GERP RS

-5.2

Varity_R

0.10

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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