1-7933198-G-A

Position:

chr1-7933198-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001561.6(TNFRSF9):c.643C>T(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TNFRSF9
NM_001561.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0920

Variant links:

Genes affected

TNFRSF9 (HGNC:11924): (TNF receptor superfamily member 9) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

TNFRSF9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFRSF9	NM_001561.6 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	7/8	ENST00000377507.8	NP_001552.2
TNFRSF9	XM_006710618.4 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	7/8		XP_006710681.1
TNFRSF9	XM_047419672.1 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	7/8		XP_047275628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNFRSF9	ENST00000377507.8 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	7/8	1	NM_001561.6	ENSP00000366729.3	Q07011
TNFRSF9	ENST00000474475.1 linkuse as main transcript	c.187C>T	p.Arg63Trp	missense_variant	2/3	3		ENSP00000465272.1	K7EJQ2
TNFRSF9	ENST00000492571.1 linkuse as main transcript	n.*285C>T		non_coding_transcript_exon_variant	5/5	3		ENSP00000464978.1	K7EJ11
TNFRSF9	ENST00000492571.1 linkuse as main transcript	n.*285C>T		3_prime_UTR_variant	5/5	3		ENSP00000464978.1	K7EJ11

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251042

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2021

This sequence change replaces arginine with tryptophan at codon 215 of the TNFRSF9 protein (p.Arg215Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs143524950, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with TNFRSF9-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.086

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.70

T;.;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

N;N;.

PrimateAI

Benign

0.18

PROVEAN

Benign

2.9

.;N;.

REVEL

Benign

0.22

Sift

Benign

0.11

.;T;.

Sift4G

Uncertain

0.053

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.23

MVP

0.47

MPC

0.094

ClinPred

0.046

GERP RS

0.70

Varity_R

0.052

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -36

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