rs148461790

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_145725.3(TRAF3):c.962G>A(p.Arg321Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000696 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

TRAF3
NM_145725.3 missense, splice_region

Scores

Splicing: ADA: 0.4330

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.05

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

TRAF3 haploinsufficiency
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

TRAF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051184654).

BS2

High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3	NM_145725.3 link	c.962G>A	p.Arg321Gln	missense_variant, splice_region_variant	Exon 11 of 12	ENST00000392745.8	NP_663777.1	Q13114-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF3	ENST00000392745.8 link	c.962G>A	p.Arg321Gln	missense_variant, splice_region_variant	Exon 11 of 12	1	NM_145725.3	ENSP00000376500.3		Q13114-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000382

AC:

AN:

251462

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000536

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000722

AC:

1055

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000688

AC XY:

500

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26136

East Asian (EAS)

AF:

0.000479

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000861

AC:

957

AN:

1112012

Other (OTH)

AF:

0.000530

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000446

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41558

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000561

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 3

Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 321 of the TRAF3 protein (p.Arg321Gln). This variant is present in population databases (rs148461790, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 569056). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

TRAF3-related disorder

Benign:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;T;T;.;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.0090

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

.;D;D;D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.051

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;L;.;.;.

PhyloP100

5.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.75

N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.31

T;T;T;T;T;D

Sift4G

Benign

0.58

T;T;T;T;T;T

Polyphen

0.016

B;B;B;B;B;.

Vest4

0.53

MVP

0.65

MPC

0.68

ClinPred

0.019

GERP RS

4.5

Varity_R

0.16

gMVP

0.90

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.43

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.48

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over