rs143813189

Positions:

chr14-102875678-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_145725.3(TRAF3):c.352C>T(p.Arg118Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,874 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 8 hom. )

Consequence

TRAF3
NM_145725.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 0.650

Variant links:

Genes affected

TRAF3 (HGNC:12033): (TNF receptor associated factor 3) The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from, members of the TNF receptor (TNFR) superfamily. This protein participates in the signal transduction of CD40, a TNFR family member important for the activation of the immune response. This protein is found to be a critical component of the lymphotoxin-beta receptor (LTbetaR) signaling complex, which induces NF-kappaB activation and cell death initiated by LTbeta ligation. Epstein-Barr virus encoded latent infection membrane protein-1 (LMP1) can interact with this and several other members of the TRAF family, which may be essential for the oncogenic effects of LMP1. The protein also plays a role in the regulation of antiviral response. Mutations in this are associated with Encephalopathy, acute, infection-induced, herpes-specific 5. [provided by RefSeq, Jul 2020]

TRAF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRAF3. . Gene score misZ 2.9892 (greater than the threshold 3.09). Trascript score misZ 4.4099 (greater than threshold 3.09). GenCC has associacion of gene with TRAF3 haploinsufficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.013559788).

BS2

High AC in GnomAd4 at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3	NM_145725.3 linkuse as main transcript	c.352C>T	p.Arg118Trp	missense_variant	5/12	ENST00000392745.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3	ENST00000392745.8 linkuse as main transcript	c.352C>T	p.Arg118Trp	missense_variant	5/12	1	NM_145725.3	P1	Q13114-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00144

AC:

361

AN:

251360

Hom.:

AF XY:

0.00128

AC XY:

174

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00211

AC:

3090

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1481

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152232

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00121

AC:

147

EpiCase

AF:

0.00213

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TRAF3: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2021	- -

Herpes simplex encephalitis, susceptibility to, 3

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
risk factor, no assertion criteria provided	literature only	OMIM	Sep 24, 2010	- -

TRAF3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T;.;T

Eigen

Benign

0.027

Eigen_PC

Benign

-0.0028

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.96

.;D;D;D;.

M_CAP

Benign

0.042

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

1.0

D;P;D;D;P

Vest4

0.86

MVP

0.69

MPC

1.6

ClinPred

0.051

GERP RS

-1.1

Varity_R

0.46

gMVP

0.87

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